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Biochem. J. (2010) 430, 379–392 (Printed in Great Britain) doi:10.1042/BJ20100396
REVIEW ARTICLE
Functional diversity of the hnRNPs: past, present and perspectives
Siew Ping HAN, Yue Hang TANG and Ross SMITH
School of Chemistry and Molecular Biosciences, University of Queensland, Building 76, Cooper Road, Brisbane, Queensland 4072, Australia
The hnRNPs (heterogeneous nuclear ribonucleoproteins) are
RNA-binding proteins with important roles in multiple aspects
of nucleic acid metabolism, including the packaging of nascent
transcripts, alternative splicing and translational regulation.
Although they share some general characteristics, they vary
greatly in terms of their domain composition and functional
properties. Although the traditional grouping of the hnRNPs as a
collection of proteins provided a practical framework, which has
guided much of the research on them, this approach is becoming
INTRODUCTION
The hnRNPs [heterogeneous nuclear RNPs (ribonucleoproteins)]
are a set of primarily nuclear proteins that bind to nascent
transcripts produced by RNA polymerase II, and which do not
stably associate with other RNA–protein complexes [1]. The
basis for this definition can be found in the history of the
experimental procedures used to isolate the hnRNPs. Originally,
sucrose density gradients were used to separate soluble RNA–
protein complexes, leading to the identification of the 40S
core particle, which comprises the hnRNPs A/B and C, and
associated RNAs [2]. Furthermore, the use of UV cross-linking to
reliably isolate RBPs (RNA-binding proteins) from intact cells
increased specificity and the range of hnRNPs detected [3].
However, the definitive list of hnRNPs was only generated by
immunopurification with monoclonal antibodies against hnRNP
C, in combination with two-dimensional gel electrophoresis [4],
which yielded a collection of 20 proteins that were named hnRNPs
A–U (Figure 1). The production of monoclonal antibodies
against specific hnRNPs provided essential tools for the isolation
of individual hnRNPs and further characterization of their
sequences and structures. In addition, immunostaining using
the same antibodies revealed that they generally had a diffuse
nucleoplasmic distribution that differed from the speckled patterns
of snRNPs (small nuclear ribonucleoproteins) or SR (serine–
arginine) proteins.
Thus the description of the defining features of hnRNPs has
evolved to incorporate new sequence, structural and functional
data. With the advent of genomic databases and bioinformatics
tools, another approach has more recently joined the fold, and the
hnRNP group of proteins has expanded as paralogues to individual
members were identified based on sequence similarities. As the
inclusion of these later members has been unsystematic and non-
uniform, this review will mostly be limited to the ‘standard’ list of
hnRNPs as set out in Figure 1. Also, hnRNPs N, S and T are poorly
characterized, apart from their identification as components of
hnRNP complexes, and thus will not be discussed further.
Abbreviations used: aRRM, atypical RNA recognition motif; A2RE, A2-response element; C/EBPα, CCAAT/enhancer-binding protein-α; ELAV, embryonic
lethal abnormal vision; hnRNP, heterogeneous nuclear ribonucleoprotein; IRES, internal ribosome entry site; KH domain, K homology domain; miRNA,
microRNA; NLS, nuclear localization signal; PCBP, poly(C)-binding protein; PTB, polypyrimidine tract-binding protein; PyT, polypyrimidine tract; qRRM,
quasi-RNA recognition motif; RBD, RNA-binding domain; RBP, RNA-binding protein; RNP, ribonucleoprotein; RRM, RNA recognition motif; SMN, survival
motor neuron; snRNP, small nuclear ribonucleoprotein; SR protein, serine–arginine protein; ssDNA, single-stranded DNA; 3 UTR, 3 -untranslated region.
1
To whom correspondence should be addressed (email ross.s@uq.edu.au).
379
increasingly incompatible with current knowledge about their
Biochemical Journal
structural and functional divergence. Hence, we review the current
literature to examine hnRNP diversity, and discuss how this
impacts upon approaches to the classification of RNA-binding
proteins in general.
Key words: functional divergence, heterogeneous nuclear
ribonucleoprotein (hnRNP), RNA-binding protein, structural
divergence.
In the present review, we describe the overall features of the
hnRNPs that have previously formed the basis for their description
as a structurally and functionally distinct group of proteins. We
then examine our current knowledge of the properties of sub-
groups of structurally similar hnRNPs, highlighting the degree of
divergence within the hnRNPs. Finally, we discuss the extent of
overlap between the hnRNPs and other RBPs, and the implications
for how we define and understand the hnRNPs.
STRUCTURAL FEATURES OF THE hnRNPs
The hnRNPs are modular proteins that usually consist of
multiple domains connected by linker regions of varying length
(Figure 1). The most prevalent domain amongst the hnRNPs,
the RRM (RNA recognition motif) [5], is characterized by a
β 1 -α 1 -β 2 -β 3 -α 2 -β 4 structure and the presence of two highly
degenerate RNP consensus sequences, RNP-1 and RNP-2 [6].
It is one of the most common protein motifs in the proteome,
and is estimated to be present in approx. 0.5–1 % of gene
products [7]. The RRM contacts RNA using the RNP-1 and
RNP-2 consensus sequences, which are present on the β 3 and
β 1 strands respectively. This involves primarily hydrophobic
interactions between four conserved aromatic protein side chains
and two bases, resulting in the binding of RNA to the β-sheet
surface. The small set of interactions and exposed binding
platform allow the RRM to bind single-stranded nucleic acids
of variable length, including ssDNA (single-stranded DNA), in a
non-sequence-specific manner. At the same time, the external β 2
and β 4 strands, linker regions, and C- and N-termini can enhance
binding affinity for specific sequences or types of nucleic acids,
with binding affinities often in the nanomolar range (reviewed in
[8]). Thus RRMs have the capacity to participate in both general
and specific interactions with nucleic acids.
It should be noted that not all hnRNPs contain canonical
RRMs. hnRNPs E/K bind RNA via the hnRNP KH (K homology)
domain, which is structurally distinct from the RRM. KH domains

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380 S. P. Han, Y. H. Tang and R. Smith
Figure 1 hnRNP structures
‘A’ represents the hnRNP A/B proteins (A0, A1, A2/B1 and A3) that are structurally similar. Gly-Rich, glycine-rich.
participate in a range of biological processes through interactions
with RNA or ssDNA. The type I KH fold, which is commonly
found in eukaryotic proteins, has a β 1 -α 1 -α 2 -β 2 -β  -α  structure
that binds nucleic acids in a cleft between the β-sheet and the
α-helices. Unlike the RRM, the KH domain can only
accommodate four bases within this narrow groove, primarily
recognises nucleic acids by hydrogen bonding and electrostatic
interactions, and binds nucleic acids with micromolar affinity
(reviewed in [9]). hnRNPs F/H contain qRRMs (quasi-RRMs),
which contain an extra β 3  loop compared with classical RRMs
and lack the RNP consensus sequences. Consequently, they have
a completely different mode of RNA recognition from the RRM
[10]. Similarly, there are five strands in the β-sheet of RRM II and
RRM III of hnRNP I {PTB [PyT (polypyrimidine tract)-binding
protein]}, and all of its RRMs lack canonical RNP motifs [11]. In
the present review, we will refer to these and other non-standard
RRMs (such as the RRM homologues of SR proteins) as atypical
(aRRMs). In addition, hnRNP U binds RNA via the glycine-rich
domain [12]. Thus the domain composition of the hnRNPs is
highly diverse, and importantly, no domain is shared across all of
the members within this protein group.
The modularity of the hnRNPs creates structural variation in
terms of domain combinations and arrangements, which in turn
generates functional diversity. As a result, the hnRNPs are highly
versatile proteins that can participate in a wide range of biological
functions (Table 1).
GENERAL CHARACTERISTICS AND FUNCTIONS
When the hnRNPs were originally described, their presence
in the same complex suggested a corresponding commonality
of structure and function. Indeed, there are several structural
features that are shared among the hnRNPs. Firstly, with the
exception of hnRNP U, all hnRNPs contain RBDs (RNA-binding
domains), often in tandem. Secondly, many of them contain
RGG boxes, which are repeats of Arg-Gly-Gly tripeptides
with interspersed aromatic amino acids. Thirdly, in addition
to RBDs, hnRNPs tend to contain auxiliary domains with
distinctive amino acid compositions, such as glycine-rich, acidic
or proline-rich domains. In addition, alternative splice variants
have been described for the majority of the hnRNPs. Moreover,

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they frequently undergo post-translational modifications, such as
phosphorylation of serine and threonine residues, and methylation
of arginine residues (reviewed in [1] and [13]).
Another key characteristic of the hnRNPs is that they undergo
nucleocytoplasmic shuttling [14]. This was originally proposed as
a means of transporting mRNA out of the nucleus, and is also es-
sential for the numerous cytoplasmic functions in which hnRNPs
participate. There are differences between the mechanisms by
which hnRNPs move across the nuclear envelope: hnRNPs A1 and
I do not contain classical NLSs (nuclear localization signals), and
their movement is coupled to transcription, whereas the shuttling
of hnRNP K, which contains an NLS, is transcription-independent
[15]. Shuttling hnRNPs undergo homomeric and heteromeric
interactions with each other, thus adding another layer of
complexity to their functional properties [16]. Although hetero-
karyon assays revealed that hnRNPs C and U did not exit the
nucleus [14], these proteins have subsequently been detected in
cytoplasmic RNA granules [17], and hnRNP C localizes to the
cytoplasm under certain cellular conditions, such as viral infection
[18].
Although these structural and shuttling properties are common
amongst the hnRNPs, they are not unique to this group of proteins.
As such, they are insufficient for distinguishing hnRNPs from
other RBPs, such as the SR proteins. Structurally, SR proteins,
similar to hnRNPs, are modular proteins that usually contain
one or more RBDs in combination with a characteristic auxillary
domain that is rich in arginine and serine residues [19].
Functionally, SR proteins are well-known antagonistic partners
with hnRNP A1 in splicing, and are also involved in other
post-splicing activities, such as mRNA export and translational
regulation [19,20]. In addition, the nucleocytoplasmic shuttling
of both hnRNPs and SR proteins is coupled to transcription [21].
These similarities in characteristics between hnRNPs and SR
proteins may reflect trends that are common to proteins involved
in mRNA metabolism.
Nucleic acid metabolism
mRNA metabolism can be partitioned into nuclear (transcription,
splicing, 5 capping and polyadenylation) and cytoplasmic
(transport, translation and degradation) components, and the
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Table 1 hnRNP functions

For clarity, functions have been categorized based on the predominant nature of the hnRNP interaction, but it should be noted that these categories are not mutually exclusive.

hnRNP DNA interactions Reference(s) RNA interactions Reference(s) Protein interactions Reference(s)

A/B/D Telomere maintenance [57–62,158,159] Splicing [42,45–55,145,160,161]

Transcription [74,162–164] Viral unspliced mRNA transport [165]
DNA replication [73] miRNA processing [69]
mRNA stability [166–170]
Translational regulation [71,171–173]
mRNA editing [174]
mRNA trafficking [35,40,63–65,67,175]
mRNA packaging [38]
C1–2 Chromatin remodelling [176] Splicing [55]
Transcription [177] mRNA retention [1]
mRNA packaging [38]
Translational regulation [82–84]
Telomere biogenesis [61]
E/K Transcription [93,95,96,101,178] Splicing [55,93,97,101,179] Signal transduction and integration [104]
Chromatin remodelling [101] Translational regulation [68,89,90,92–94,99–101]
Telomere biogenesis [61,101] mRNA stability [86–89,94,98,101]
F/H mRNA stability [108] Splicing [110,127]
Splicing [10,56,110,111,138]

G DNA repair [132] Splicing [55,129,130,180]

Tumour suppressor [132]
Transcription factor [131,132]
I/L Transcription [181] Splicing [55,111,112,115–118,122–124,
127,182,183]
mRNA export [184]
Translation regulation [120,125,126,185]
mRNA stability [119,121,125,185]
Polyadenylation [184]
M Splicing [55] Antigen receptor (only for the M4 isoform) [33]
Heat-shock response [31] Thyroglobulin receptor (only for the M4 isoform) [33]
P Transcription [140] Splicing [55,141] Cell spreading and stress response [37]
Genome stability [186] Transcription [141]

Q/R Splicing [146,187]

RNA replication [188]
mRNA stability [189]
mRNA trafficking [36,190]
U Chromatin organization [191] RNA binding [192] Transcription [192,193]
DNA binding [192]

nucleocytoplasmic shuttling of hnRNPs provides an essential
avenue for the coupling of the two compartments. Consequently,
the hnRNPs participate in virtually every step of this process
(Figure 2), and also in other aspects of nucleic acid processing,
such as telomere maintenance, chromatin remodelling and DNA
repair. There is considerable overlap between the functions of
different hnRNPs, particularly between paralogues, but they are
not functionally redundant. Many of the biological functions
ascribed to the hnRNPs involve dynamic and co-operative
interactions within large numbers of proteins, and it is likely
that the different binding affinities of the hnRNPs target them to
distinct nucleic acid and protein targets within these assemblages.
For instance, the range and specificity of alternative splicing
reactions differs between hnRNPs, and different sets of hnRNPs
assemble on each mRNA as they undergo transport and maturation
[22,23]. Thus hnRNPs have both generalised roles as RNA
packaging proteins, and specialised roles that are dependent on
specific RNA–protein or protein–protein interactions.
RNA binding
The dual nature of the hnRNPs as both generalists and specialists
is perhaps most evident in their RNA-binding properties. hnRNPs
bind, in vitro, to a wide variety of RNA and ssDNA sequences
in a manner resistant to salt or heparin treatment [1]. However,
more stringent assays using salt concentrations of up to 2 M NaCl
revealed distinct binding affinities, and distinct binding motifs
were identified using SELEX (systematic evolution of ligands
by exponential enrichment) [24,25]. Subsequently, more specific
binding sequences were identified for each of the hnRNPs using
different experimental setups in a range of functional contexts
(Table 2). The conclusions drawn from such assays are highly de-
pendent on the experimental conditions utilized, as protein–RNA
interactions are highly dynamic, and RNA secondary structure is
greatly influenced by environmental factors, such as the presence
of ions [26,27]. The methods used to study these interactions,
especially in earlier approaches, may not be representative of
actual intracellular conditions. In addition, techniques based on
the crude separation of RNA–protein complexes by size or density
cannot distinguish between sets of proteins bound to different
mRNAs. Moreover, although the hnRNPs, in particular hnRNPs
A/B and C, are among the most highly expressed proteins in
the cell, with levels comparable with those of the histones [1],
their distribution is not uniform within the cell. Thus local protein
concentrations, as well as those of accessory binding partners,
may influence the nature of their binding.


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382 S. P. Han, Y. H. Tang and R. Smith

Figure 2 Nuclear and cytoplasmic functions of hnRNPs at multiple stages of mRNA metabolism
(1) Packaging of nascent RNA transcripts. (2) Regulation of constitutive and alternative splicing. (3) Assembly of A2RE-containing mRNAs into RNA granules for trafficking, followed by localized
translation of trafficked mRNAs at distal sites. (4) Regulation of mRNA stability. (5) Activation or silencing of mRNA translation. Note that not all hnRNPs participate at each of these stages. Please
refer to Table 1 for specific functions of each hnRNP. An animation of this Figure is available at http://www.BiochemJ.org/bj/430/0379/bj4300379add.htm.

Intracellular localization
The hnRNPs generally have a diffuse nucleoplasmic distribution
but are excluded from nucleoli. In addition, hnRNP L is localized
to discrete non-nucleolar foci associated with chromosomes [28].
hnRNP I is also found within nuclear foci, but each nucleus
usually only contains a single perinucleolar structure [29]. The
hnRNPs F/H and M exhibit a speckled pattern similar to, but
distinct from, the distribution of snRNPs [30,31], whereas the
intranuclear localization of hnRNP G and its paralogues appear
to overlap with that of SR proteins [32].
Although hnRNPs are mostly expressed in the nucleus, there are
a few exceptions to the rule. One of the isoforms of hnRNP M is a
membrane-bound receptor [33], whereas hnRNP Q (SYNCRIP)
is predominantly cytoplasmic [34]. Additionally, the limited
localization of certain hnRNPs to the cytoplasm can also be
of functional importance. For instance, hnRNP A2/B1 and Q
are present in mRNA granules and regulate mRNA trafficking
[35,36], whereas hnRNP P (FUS) is localized to cytoplasmic
stress granules and participates in the cellular stress response [37].
It should be noted that the characterization of hnRNP localization
patterns has mostly been conducted in HeLa cells, which are
human epithelial (cervical carcinoma) cells, and it would be
interesting to see if different patterns are observed in other species
and cell types.
STRUCTURAL AND FUNCTIONAL DIVERGENCE OF THE hnRNPs
The coverage of hnRNPs in the current literature is highly
uneven, with detailed and extensive research into the more popular
hnRNPs, and almost no information available about the rest. The
following section reviews our current understanding of the better-
known sets of hnRNPs, and highlights some of their functional
and structural correlations with each other.
hnRNPs A/B
The hnRNPs A/B comprise four paralogues: A1, A2/B1, A3
and A0. With the exception of hnRNP A0, for which there is
little functional data in the current literature, the hnRNPs A/B
are known to be involved in many aspects of RNA processing.
hnRNPs A/B, in combination with hnRNP C, package nascent
transcripts in a non-sequence-specific manner [38]. At the same
time, the hnRNPs A/B also have distinct and specific preferences


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 hnRNP diversity 383

Table 2 hnRNP-binding sequences and the functional contexts in which II), neurogranin and Arc [67]. In addition, hnRNP A2/B1 recruits
they were identified hnRNP E1 to RNA granules, which inhibits translation of
trafficked mRNAs until they reach their intended destination [68].
hnRNP Binding sequence Functional context Reference(s) The recently discovered, and highly unexpected, role of hnRNP
A1 in miRNA (microRNA) regulation highlights the astounding
A1 UAGAGU, UAGGGU, UAGRG(A/U), Alternative splicing [41–43] functional diversity of this protein. hnRNP A1 binds human
UAGAGA, UAGG, GGGU, UGGGGU
AU-rich mRNA stability [166]
pri-miR-18a and is required for efficient processing of the
A2/B1 GCCAAGGAGCC mRNA trafficking [66] miRNA precursor by Drosha [69]. In addition, it accumulates
TTTAGGG Telomere maintenance [59] in cytoplasmic stress granules, in stress-activated cells, and is
A3 GCCAAGGAGCC mRNA trafficking [40] required for recovery from stress [70]. Cellular stress can also
G-rich, GGCAG repeats, TTAGGG Telomere maintenance [62,159,194] induce the cytoplasmic redistribution of hnRNP A1, whereupon
repeats it acts as an IRES (internal ribosome entry site) trans-acting factor
C U-rich Translation [83]
D UUAGG Alternative splicing [194]
[71]. Besides this, hnRNP A1 can disrupt steroid hormone signal
AUUUA mRNA stability [195] transduction by suppressing the activity of vitamin D receptor,
TTAGGG repeats Telomere maintenance [194,196] thus contributing to vitamin D resistance [72]. Furthermore,
E UUAGG Alternative splicing [194] hnRNP A1 binds directly to and stimulates the nuclease activity
C-rich mRNA stability and translation [197] of FEN-1 (flap endonuclease-1), thus increasing the efficiency
TTAGGG repeats Telomere maintenance [194] of Okazaki fragment maturation during DNA replication [73].
CU-rich elements Translational silencing [198]
F/H G-tract, GGGA Alternative splicing [10,43,109]
Rounding off this remarkable but non-exhaustive list is the role
G-rich Translational regulation [108] of hnRNP A1 in regulating APOE (apolipoprotein E) promoter
G CC(A/C)-rich, AAGU Alternative splicing [130,199] activity, which is important in the development of coronary heart
I UCUUC, UCUU, CUCUCU, Alternative splicing [200–203] disease and Alzheimer’s disease [74].
CUUCUCUCU
K dCdT elements Transcription [204]
L CA repeats RNA stability [121]
U AT-rich Chromatin organization [191]
hnRNP C and Raly
hnRNP C is the founding member of the hnRNPs, and was
also the first hnRNP implicated in splicing [75]. There are two
human spliceoforms, C1 and C2, which differ by 13 residues
for RNA sequences [1,23,39–43]. This seemingly contradictory [76]. Interestingly, mouse hnRNP C has four spliceoforms, thus
behaviour may depend upon the effective local concentration of suggesting that species-specific splicing may be common among
the hnRNPs A/B, as they are among the most abundant proteins the hnRNPs [77]. hnRNP C contains an N-terminal RRM, a C-
in the cell and are often present in molar excess over their high- terminal auxiliary domain that is rich in acidic residues [78],
affinity binding targets [44]. and a leucine zipper motif that promotes oligomerization [79,80].
hnRNPs A1 and A2/B1 have been well-characterized as C13 C2 tetramers bind RNA in a non-sequence-specific manner
splicing repressors that promote distal splice site selection, and to form an hnRNP C–RNA complex, which is the obligate first
regulate the alternative splicing of many mRNAs, including those event in the assembly of the 40S core particle [38]. From 230
for β-globin, NMDA (N-methyl-D-aspartate) receptor, HIV-1, to 240 nucleotides of RNA loop around each C13 C2 tetramer,
Src, survival of motor neuron, follicle-stimulating hormone β with the RNA binding to exposed RNPs on the surface of the
subunit, neurofibromatosis and BRCA1 (breast cancer early-onset tetramer. Surprisingly, mouse cells that do not express detectable
1) [45–54] (see also [55] for a review). However, they apparently levels of hnRNP C (due to insertion of a provirus into the gene)
can also promote exon inclusion [56], which demonstrates the are still viable, do not exhibit any aberrations in gene expression,
context-dependency of splice regulation. Interestingly, A1 also and can differentiate in vitro, albeit more slowly than wild-type
modulates alternative splicing of its own pre-mRNA by binding cells [77]. This implies that other proteins can compensate for
multiple intronic splicing silencer elements that flank alternative hnRNP C in the biologically indispensable process of mRNA
exon 7b [41,42]. Efficient splicing requires the presence of biogenesis. This kind of functional redundancy is not uncommon
multiple hnRNP A1 recognition motifs, which suggests that among the hnRNPs and other RBPs. However, hnRNP C-deficient
hnRNP A1 proteins may act co-operatively to suppress exon mice do not survive embryonic development, presumably because
inclusion, perhaps by looping out the pre-mRNA such that internal their cells cannot meet the heightened metabolic demands during
5 splice sites are repressed [41,43]. this period of rapid growth [77]. Similarly, mice that do not
In addition, hnRNPs A1, A2/B1 and A3 bind to both single- express Raly (hnRNP associated with lethal yellow), which shares
stranded telomere DNA and telomerase RNA, and may act
as molecular adapters that regulate the interactions between a high level of sequence similarity with hnRNP C, do not survive
telomerase and telomeres [57–60]. Also, the hnRNPs A/B, embryonic development [81].
in concert with other hnRNPs and telomere-binding factors, Besides its role in the packaging of nascent transcripts, hnRNP
may influence the higher order structure of the telomere and C also increases mRNA translation by binding the IRES of
protect it from degradation or regulate access to telomerase, thus mRNAs such as those encoding c-Myc, Unr (upstream of N-Ras)
maintaining genome stability [61,62]. and c-sis [82–84]. Although hnRNP C is generally thought of as
hnRNP A2/B1 is well-characterized as an mRNA trafficking having wholly nuclear functions, its binding to IRESs occurs in the
trans-acting factor in both oligodendrocytes and neurons [35,63]. cytoplasm, and this cytoplasmic localization is usually triggered
It recognises the A2RE (A2-response element), a 21-nucleotide by entry into mitosis [82–84].
cis-acting element present in myelin basic protein mRNA [64,65].
hnRNP A2/B1 is necessary and sufficient for the process of
hnRNPs E/K
localization of myelin basic protein mRNA [66], as well as
other mRNAs containing A2RE-like sequences, such as those The hnRNPs E/K, which include hnRNPs E1, E2 and K, are
encoding CaMKII (Ca2+ /calmodulin-dependent protein kinase markedly different from the other hnRNPs in that they contain


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384 S. P. Han, Y. H. Tang and R. Smith
three KH domains instead of RRMs or RRM-like domains. Owing
to their binding affinities, hnRNPs E1 and E2 are often known
as PCBPs [poly(C)-binding proteins] 1 and 2, and, based on their
sequences, they should logically be grouped together with closely-
related paralogues PCBPs 3 and 4 in the same protein family [85].
It should be noted, though, that PCBPs 3 and 4 are cytoplasmic,
and are not classified as hnRNPs.
Although the hnRNPs E1 and E2 are highly expressed within
cell nuclei, most work has centred on their cytoplasmic roles in
regulating mRNA stability and translation. They are assembled
into complexes that stabilize mRNAs via interactions with PABP
[poly(A)-binding protein] [86]. Their mRNA targets include
transcripts for C/EBPα (CCAAT/enhancer-binding protein-α),
which regulates granulocyte differentiation [87], and androgen
receptor, which may play a role in carcinogenesis [88]. In addition,
hnRNPs E1 and E2 are IRES-binding factors that enhance
translation of target mRNAs [89,90]. It has been suggested that
binding of hnRNP E1 unfolds the secondary structure of the
mRNA to allow access to ribosomes [90]. In contrast, hnRNP E1
inhibits translation of trafficked mRNAs in transit within RNA
granules [68], and silences lipoxygenase mRNA by binding to
its 3 UTR (3 -untranslated region) in a complex with hnRNP K
[91,92]. The role of hnRNP E1 in integrating manifold aspects of
gene expression and co-ordinating them with signal transduction
pathways is exemplified in its regulation of the transcription,
splicing and translation of p21-activated kinase 1 in response
to mitogens [93]. Likewise, hnRNP E2 is involved in multiple
steps in the poliovirus replication cycle, including regulation of
the stability, translation and replication of polioviral mRNA [94].
Similarly, hnRNP K has a wide range of nuclear and
cytoplasmic functions, including mRNA silencing [91,92],
transcription [95,96], splicing [97], and regulation of mRNA
stability [98] and translation [99,100]. Importantly, hnRNP K
regulates expression of translation initiation factor 4E and Myc,
which have many downstream targets and global effects on
cellular physiology [96]. The functional versatility of hnRNP
K arises from its modular structure. Its three KH domains
can interact with both RNA and ssDNA, and it also contains
a K interactive region that can recruit a variety of proteins,
including kinases and factors regulating transcription, splicing
and translation [101]. In this way, hnRNP K acts as a
‘docking platform’ to co-ordinate nucleic acid metabolism and
mediate cross-talk between signalling pathways [101]. Its role in
integrating cellular signals is important in several key pathways,
including the p53 transcriptional response to DNA damage [102]
and the mitochondrial response to insulin [103]. Thus hnRNP K
is at the centre of a vast interaction network, with 114 binding
partners having been identified via affinity purification coupled
with MS [104].
hnRNPs F/H
The hnRNPs F/H include hnRNPs F, H1 (H), H2 (H ) and H3
(2H9). Unlike most hnRNPs, which can bind both RNA and
ssDNA independently of sequence, the hnRNPs F/H appear to
be specific for poly(G) tracts [30]. Their RBDs differ from those
in most other hnRNPs, in that the residues that contact RNA in
standard RRMs are not conserved [30]. Thus the RBDs of the
hnRNPs F/H have been described as qRRMs [105]. Three qRRMs
are present in each protein, of which qRRM 3 assumes the
canonical RRM fold, whereas qRRMs 1 and 2 are structurally
distinct from, and have a RNA-binding surface that is more
exposed, than that of standard RRMs [10]. This may be required
due to the stability of G-rich secondary structures, which would
tend not to adopt the extended configuration necessary for binding

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to a typical RRM β-platform. Rather surprisingly, qRRMs are
deleted from three and severely truncated in one of the six known
splice variants of hnRNP H3 [106], which implies that these
spliceoforms do not directly participate in RNA metabolism.
Although the hnRNPs F/H are highly similar in sequence,
structure and binding preferences, they are differentially regulated
by treatment with phorbol esters, which reduce expression of
hnRNP F but not H1 or H2 [105]. They are also differentially
expressed in both normal and cancerous tissues [107], antagonize
each other in the regulation of polyadenylation of mRNAs
[108], and have different binding specificities for gene regulatory
elements [109]. Notably, hnRNP F is predominantly cytoplasmic,
whereas hnRNPs H1 and H2 are mostly nuclear [107]. This feature
of overlapping but distinct functionality between paralogues is
common amongst the hnRNPs.
The hnRNPs F/H are perhaps best known for their role in
regulation of alternative splicing, where interactions between
multiple hnRNPs bound to target sites causes looping out
of intervening introns [56] (the same mechanism has also
been proposed for the hnRNPs A/B [41,43]). In addition,
hnRNP F regulates polyadenylation site choice in the alternative
splicing of immunoglobulin heavy chain pre-mRNA by blocking
recruitment of cleavage stimulation factor, thereby promoting the
differentiation of memory cells into B-cells [110]. As the ratio of
hnRNP F to hnRNPs H1 and H2 is decreased in memory cells
compared with B-cells, and these proteins have been shown to
form heteromers, hnRNPs H1 and H2 may sequester hnRNP F
and prevent it from promoting differentiation [110]. In addition,
these proteins are present together with hnRNP I in a neuronal
splicing enhancer complex that assembles on c-src mRNA [111].
hnRNP I (PTB)/hnRNP L/nPTB
hnRNP I is more commonly known as PTB because it regulates
splicing by binding to the PyT at the branch point upstream of
exons [112]. It contains four RRMs, as does the highly similar
hnRNP L [29]. There are conflicting reports about the involvement
of each RRM to RNA binding. Oh et al. [113] proposed that only
RRMs 3 and 4 contributed to RNA binding, and that RRM 2
promoted oligomerization. In contrast, Simpson et al. [11] found
that hnRNP I exists as a monomer, and all its RRMs bound
RNA. The latter result was supported by Vitali et al. [114], who
established that RRMs 1 and 2 act independently of each other and
therefore have substantial substrate flexibility, whereas RRMs 3
and 4 participate in unusually rigid domain–domain interactions
to create an RNA-binding platform that induces formation of RNA
loops.
The mechanism by which hnRNP I represses splicing has
been examined by Sharma et al. [115] in a particularly elegant
illustration of splicing dynamics. Splicing requires a shift from
exon definition, during which splicing and other accessory factors
mark out exon boundaries, to the assembly of an intron-defined
spliceosome, which catalyses the splicing reaction. This involves
a number of transitions through a defined series of spliceosomal
complexes of varying protein compositions. hnRNP I inhibits
the interaction of splicing factors bound to exons upstream and
downstream of branch points, thus causing splicing to be arrested
at the pre-spliceosomal A complex. In addition, hnRNP I represses
exon inclusion by competing with splicing factor U2AF65 for
binding to the PyT [116], and may also act by looping out
exons flanked by PyTs [117]. Importantly, hnRNP I can induce
either exon inclusion or skipping, depending on the position of its
binding site relative to the splice site [118].
The pyrimidine-rich sequences to which hnRNP I preferentially
binds are common in other mRNA regulatory elements that

control mRNA stability and translation. Stimulation of pancreatic
β-cells triggers the translocation of hnRNP I to the cytosol, where
it stabilizes mRNAs encoding proteins that form insulin secretory
granules, thus promoting insulin secretion [119]. Besides this,
during apoptosis, hnRNP I binds the IRESs of a subset of mRNAs,
thereby rendering them resistant to translational inhibition [120].
hnRNP L preferentially binds to CA repeats [121]. It regulates
the inducible exon skipping in CD45 mRNA in response to
T-cell activation, possibly via the stabilization of snRNP binding
[122,123]. hnRNP L also regulates the alternative splicing of
other genes via additional mechanisms, including intron retention,
suppression of multiple exons and alternative poly(A) site
selection [124]. Both hnRNP I and L interact with the 3 UTR
of inducible nitric oxide synthase mRNA, and may regulate its
stability [125]. Furthermore, both hnRNP L and PTB may co-
operatively regulate translation of Cat-1 mRNA during amino
acid starvation [126].
nPTB is a truncated paralogue of hnRNP I that is expressed in
vertebrate neuronal cells, and both hnRNP I and nPTB assemble
into common splicing complexes (along with the hnRNPs F/H)
[111,127]. However, as nPTB has higher binding affinity, but
lower splicing activity, than hnRNP I, the expression of nPTB
reduces splicing repression by hnRNP I [127]. Thus differential
expression of closely-related proteins with divergent functional
properties results in species- and tissue-specific regulation of RNA
metabolism.
hnRNP G/GT and RBMY
hnRNP G (also known as RBMX, which refers to the location of its
gene on the X chromosome), is unique in that it is to date the only
hnRNP shown to be glycosylated [128]. It contains an N-terminal
RRM and a C-terminal auxiliary domain that is rich in glycine
and basic residues [128]. Depending on the mRNA substrate,
hnRNP G can act synergistically with or antagonistically to
Tra2β, a splicing factor, to regulate inclusion of alternative
exons [129,130]. In addition, hnRNP G promotes the expression
of tumour suppressor Txnip, and protects DNA double-strand
breaks from further degradation, thus reducing tumorigenicity
and maintaining genomic stability [131,132].
RBMY is the Y chromosome counterpart of hnRNP G, whereas
hnRNP GT is thought to have originated from retrotransposition
of hnRNP G [32,133]. Unlike hnRNP G, which is ubiquitously
expressed, RBMY and hnRNP GT are primarily expressed in
the testis [133,134]. All three proteins have been shown to
interact with SR proteins and Tra2β, and to inhibit splicing by
the latter [32]. RBMY contains four sets of SRGY-rich repeats
(SRGY boxes), which are characteristic of the RS (arginine–
serine) domains of SR proteins, and localizes to intranuclear
concentrations of SR proteins known as SR speckles [32]. hnRNP
G also contains one SRGY box, which suggests that it may
also have properties that resemble those of the SR proteins. It is
therefore tempting to speculate that if hnRNP G had not already
been described as an hnRNP, it and its paralogues might have
been classified as SR proteins instead.
CLINICAL SIGNIFICANCE OF THE hnRNPs
Given their central roles in the regulation of gene expression, it
is not surprising that the hnRNPs have been linked to numerous
diseases. Many of the hnRNPs have been directly or indirectly
implicated in cancer development, and aberrant expression of
hnRNPs is characteristic of various types of cancer [135,136].
Dysregulation of hnRNP function contributes to carcinogenesis
in multiple ways (Figure 3). Many hnRNPs are involved in
hnRNP diversity 385
telomere biogenesis, and deviations in telomere length can
lead to tumorigenesis [61]. Defects in mRNA splicing are also
common in cancer development, and changes in the activity of
splicing factors, such as hnRNPs A1 and F/H, could lead to
mis-splicing of their mRNA targets, which include regulators
of cell proliferation such as c-Src and CD44 [50,111,137,138].
Similarly, the transcriptional and translational regulatory targets
of hnRNPs E/K include c-Myc, the androgen receptor, eIF4E
(eukaryotic translation initiation factor 4E), p53 and C/EBPα
[87,88,96,100,102,139], for which changes in expression levels
could lead to excessive cell proliferation. In addition, hnRNP
G reduced tumorigenicity in oral carcinoma cells by upregulating
thioredoxin-interacting protein, a tumour suppressor [131]. On the
other hand, hnRNP M4 interacts with carcinoembryonic antigen,
a cell membrane receptor that may contribute to metastasis in
colorectal cancer [33]. Finally, chromosomal translocations
in multiple types of cancer, including leukaemias and sarcomas,
create chimaeric oncoproteins in which FUS (hnRNP P) is fused
to transcription factors [140–143].
Recently, mutations in the FUS gene itself have been linked
to familial amyotrophic lateral sclerosis, revealing a novel role
for FUS in neurodegeneration [144]. Another neurodegenerative
disease associated with the hnRNPs is spinal muscular atrophy,
which is caused by loss of the SMN1 (survival motor neuron
1) gene. SMN2, a nearly identical gene copy, undergoes exon
skipping to produce truncated and functionally deficient SMN
protein. As this exon skipping is regulated by hnRNPs A1, G and
Q/R, they could potentially be therapeutic targets for this common
genetic disease [129,145,146]. Furthermore, hnRNP A2/B1 has
been implicated in Alzheimer’s disease, and expression of its
isoforms is altered in the hippocampi of patients at different stages
of the disease [147].
Although many of the hnRNPs play significant roles in the
development of cancer and neurodegeneration, it is important
to note that different hnRNPs contribute to disease progression
via distinct mechanisms, and exert their effects via pathways
involving different sets of genes. Furthermore, these pathways in-
volve multiple RBPs, thus placing the hnRNPs within an
interconnected network of functionally related proteins.
OVERLAPPING FEATURES OF hnRNPs AND OTHER RBPs
The hnRNPs have many features in common with other RBPs,
such as the SR proteins and ELAV (embryonic lethal abnormal
vision)-like proteins. Structurally, they comprise multiple RBDs,
in particular the RRM, and often also contain auxiliary domains
(Figure 4). Functionally, they have multiple and overlapping
roles in the regulation of alternative splicing, mRNA stability,
mRNA export and other aspects of post-transcriptional processing
[148,149]. In addition, they are ubiquitously expressed, and most
shuttle between the nucleus and cytoplasm [13,21,150,151].
Although the hnRNPs, SR proteins and ELAV-like proteins
have many similarities at both the structural and functional
level, they have generally been described and studied as separate
protein families. The basis for this has more to do with the
history of the field, rather than phylogenetic, structural or
functional evidence. The uncertainty over the delineation of
what distinguishes hnRNPs from other RBPs has prompted
repeated calls for a redefinition of hnRNPs [1,44,55]. The original
definition of hnRNPs was mainly operational and was based on the
experimental methods available at the time. Although this scheme
has provided a useful conceptual framework for studying RNA–
protein interactions, it is difficult to reconcile with our current
knowledge of RBP diversity, function and evolution, and has

c The Authors Journal compilation 
c 2010 Biochemical Society
386 S. P. Han, Y. H. Tang and R. Smith

Figure 3 hnRNPs can contribute to carcinogenesis

Note that pathways (1)–(3) can involve multiple hnRNPs, whereas pathways (4) and (5) are specific for hnRNP M4 and Fus (hnRNP P2) respectively. (1) Deviations in telomere biogenesis result
in genome instability. (2) Defects in splicing regulation result in mis-splicing of transcripts involved in cellular proliferation and differentiation, which could alter cell-cycle regulation. (3) Changes
in gene expression at the transcriptional or translational level can up- or down-regulate expression of oncogenes or tumour suppressors. (4) hnRNP M4 interacts with cell membrane receptors to
trigger signalling pathways that promote metastasis. (5) Chromosome translocations involving FUS create chimaeric proteins that act as oncoproteins. Please see text for further details.

Figure 4 Modular structure of selected hnRNPs and other RBPs

Glu-Rich, glycine-rich; Arg/Ser Rich, ariginine- and serine-rich.


c The Authors Journal compilation 
c 2010 Biochemical Society

a limited basis in terms of structural, functional or expression
characteristics.
However, the description of hnRNPs as a family has slipped into
common usage, thus implying that they have a common ancestry
and shared functional properties (although it should be noted that
most of the long-standing research groups in this field are usually
careful not to describe them as such). This has resulted in cases
in which experimental findings based on a subset of hnRNPs are
extrapolated to all members of the group, which may be confusing
and potentially misleading. In addition, the identification of novel
hnRNPs based on structural similarity to a subset of hnRNPs
has led to a growing list of members, but the rules for inclusion
remain ambiguous and inconsistent [55]. As existing approaches
do not seem to adequately address the structural, functional and
evolutionary features of the RBPs, it is important to be aware of
these limitations when interpreting the current literature.
CONCLUSIONS AND PERSPECTIVES
The hnRNP proteins were initially viewed as prime constituents
of 40S heterogeneous nuclear ribonucleoprotein particles, which
bind to and stabilize nascent pre-mRNA. However, more recent
findings have shown that the functions of these proteins extend
far beyond the packaging of nascent RNA, and they are now
viewed as a highly divergent group of proteins with roles in many
important aspects of nucleic acid metabolism.
Functional variation within the hnRNPs can arise from
expression of multiple paralogues and alternatively-spliced
isoforms. However, paralogues and isoforms are often ascribed
parallel functions, often in the absence of extant data. For example,
hnRNPs A1 and A2/B1 have some common functions, with
both being implicated in telomere maintenance and regulation
of cell proliferation. However, hnRNP A2/B1 is important in
cytoplasmic RNA trafficking, whereas there is no evidence for
the involvement of hnRNP A1 in this process. Likewise, there is
functional discrimination between hnRNP A2 isoforms: although
the majority of the hnRNP A2 isoforms are spatially restricted
to the nucleus, we have recently shown that only one minor
isoform, A2b, is associated with the formation of RNA granules
that undergo cytoplasmic trafficking [152]. Thus it will be
important to determine if other hnRNPs have paralogue- or
isoform-specific locations and functions.
To better understand the functional roles of the hnRNPs, further
studies of their three-dimensional structures are required, and
more effort needs to be invested in attempts to crystallize RBPs
and their complexes with nucleic acids. In particular, we need
to address the question of whether the protein, nucleic acid or
both adopt a modified structure in the protein–RNA complex.
The three-dimensional structures of several modules of hnRNPs
have been solved to high resolution [10,57,114,153–155]. The
GRD (glycine-rich domain), which is a common domain in
the hnRNPs and other RBPs, introduces two complications for
crystallographic studies. First, it lowers protein solubility and
therefore impedes ready crystallization. Secondly, this unusual
amino acid sequence is predicted to form flexible loops (omega
loops) [156] that are pinned together on a backbone and would
not be conducive to crystal formation. For these reasons, to date,
most of the solved hnRNP structures are of individual or tandem
domains, and none have been of intact proteins.
Besides protein structures, RNA structures would provide
further information about the nature of RNA binding to the
hnRNPs and other RBPs. Tiedge [157] has predicted that
many RNA elements form three-dimensional spatial codes,
described as kink–turn motifs. Thus, in order to understand the
hnRNP diversity 387
features of cis-acting elements that facilitate their association
with trans-acting factors, and consequently the molecular basis
for recognition, we need to determine their three-dimensional
structures. For example, mutational analysis has revealed partial
clues to how the A2RE interacts with hnRNP A2/B1, but in
the absence of complete structural data, our knowledge falls
short of explaining their binding at the atomic level. In contrast,
X-ray crystallographic studies have shown that binding of hnRNP
A1 with the telomere repeat, which forms a single-stranded G-
rich overhang, involves telomeric repeat bases interacting with
hydrophobic residues that are on the β1 and β3 strands of the
RRM module [57]. The identification of specific nucleotides
and residues critical for the telomere–hnRNP A1 interaction
will provide valuable information about RNA–protein binding
in general, and facilitate future experimental design.
Bioinformatics approaches have been useful in expanding the
library of hnRNP paralogues and isoforms. This has paved the
way for further studies of their three-dimensional structures in
order to better understand the functions and regulation of these
biologically important, multi-functional proteins. The greatest
need is to identify and characterize their alternatively spliced
isoforms, at the sequence, structural and functional level. To
complete the picture of molecular recognition, complementary
information is also needed for the cis-acting elements. The
three-dimensional structures of these cis-elements are complex:
progress has been made in predicting nucleotide sequences that
will bind specified trans-acting factors, but the details of cis-
element association with proteins remain largely obscure.
In light of the functional complexity of the hnRNPs, the
continued utility of the existing definition of the hnRNPs is
questionable, given the lack of commonality within the hnRNPs
and their lack of distinction from other RBPs. The prevalence
of isoforms adds to the complexity of the nomenclature, which
requires resolution. Ideally, the classification of hnRNPs and other
RBPs should be based on current knowledge of the structural and
functional properties of these proteins, and accurately describe
relationships based on objective and consistent measures. This
could incorporate approaches based on their evolutionary histories
and homology, or domain-centric approaches that reflect the
highly modular nature of these proteins. We envisage that a more
logically coherent and robust approach to the classification of
hnRNPs and other RBPs will facilitate a global understanding
of the functional diversity of these key transcriptome regulators.
Note added in proof (received 23 July 2010)
There has been a recent classification of SR proteins as described
by Manley and Krainer [205].
ACKNOWLEDGMENTS
We thank Dr Sam Lukowski for helpful feedback.
FUNDING
This work was supported in part by a grant from the Cancer Council of Queensland to R.S.
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Received 22 March 2010/29 June 2010; accepted 29 June 2010
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