RNA Biology

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Cajal bodies and their role in plant stress and

disease responses

Andrew J. Love, Chulang Yu, Natalia V. Petukhova, Natalia O. Kalinina,

Jianping Chen & Michael E. Taliansky

To cite this article: Andrew J. Love, Chulang Yu, Natalia V. Petukhova, Natalia O. Kalinina,
Jianping Chen & Michael E. Taliansky (2017) Cajal bodies and their role in plant stress and
disease responses, RNA Biology, 14:6, 779-790, DOI: 10.1080/15476286.2016.1243650

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RNA BIOLOGY
2017, VOL. 14, NO. 6, 779–790
https://doi.org/10.1080/15476286.2016.1243650

REVIEW

Cajal bodies and their role in plant stress and disease responses
Andrew J. Lovea, Chulang Yub, Natalia V. Petukhovaa, Natalia O. Kalininac, Jianping Chenb, and Michael E. Talianskya,b
a
Cell and Molecular Sciences, James Hutton Institute, Invergowrie, Dundee, UK; bState Key Laboratory Breeding Base for Sustainable Pest and Disease
Control, Key Laboratory of Biotechnology in Plant Protection of MOA and Zhejiang Province, Institute of Virology and Biotechnology, Zhejiang
Academy of Agricultural Sciences, Hangzhou, China; cA.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University,
Leninskie Gory, Moscow, Russia

ABSTRACT ARTICLE HISTORY

Cajal bodies (CBs) are distinct sub-nuclear structures that are present in eukaryotic living cells and are often Received 1 August 2016
associated with the nucleolus. CBs play important roles in RNA metabolism and formation of RNPs involved Revised 19 September 2016
in transcription, splicing, ribosome biogenesis, and telomere maintenance. Besides these primary roles, CBs Accepted 27 September 2016
appear to be involved in additional functions that may not be directly related to RNA metabolism and RNP KEYWORDS
biogenesis. In this review, we assess possible roles of plant CBs in RNA regulatory pathways such as Abiotic stress; Cajal bodies;
nonsense-mediated mRNA decay and RNA silencing. We also summarize recent progress and discuss new plants; plant viruses; PARP
non-canonical functions of plant CBs in responses to stress and disease. It is hypothesized that CBs can
regulate these responses via their interaction with poly(ADP ribose)polymerase (PARP), which is known to
play an important role in various physiological processes including responses to biotic and abiotic
stresses. It is suggested that CBs and their components modify PARP activities and functions.

Introduction cues.9,14-17 Indeed, different types of stress, such as UV irradiation,

heat shock, transcriptional inhibition, osmotic stress, starvation,
Cajal bodies (CBs) are highly conserved sub-nuclear structures
and viral infection may induce re-arrangements of CBs (such as
which are often found physically and functionally associated with
their number, integrity, structure and architecture).18 In addition
the nucleolus (Fig. 1).1-7 They range in size from 0.2 – 2 mm
to being responsive to such cues, it has been suggested that CBs
(depending on the organism) and 1 – 6 of them may be present in
could perhaps participate in the transduction of these signals and
a typical nucleus (usually 1-2 in a plant nucleus). CBs are dynamic
also those of other biological processes such as cell cycle, develop-
membrane-less structures which can split into daughter bodies or
ment and abiotic stress mitigation,18 gene silencing and non-sense
can fuse together, or localize to nucleoli or move to other parts of
mediated decay (reviewed in 19); suggesting new and unexpected
the nucleus.8,9 They have been found to play important roles in
functions for these sub-nuclear compartments. Moreover, in just
RNA metabolism and formation of ribonucleoprotein particles
the past decade CBs have been discovered to play a critical role in
(RNP) involved in transcription, splicing, ribosome biogenesis, and
modulating some virus infections,20,21 either by providing viruses
telomere maintenance. In spite of such complexity and multifunc-
with some functions required for their replication, or by enhancing
tionality, CBs per se are not normally essential for cell survival in
host defense mechanisms against viruses. Thus, these enigmatic
either animal or plant organisms.4,7 However, in some exceptional
sub-nuclear bodies are emerging as highly complex and multifunc-
circumstances such as during embryogenesis in mice and zebrafish,
tional regulatory compartments, and model systems including
functional CBs are absolutely required for completion of this devel-
plants, have implicated CBs in a surprisingly diverse range of bio-
opmental process and concomitant cell survival.10,11 It is widely
logical mechanisms which we are only just beginning to under-
accepted that the reason why cells can generally survive without
stand. Since several excellent reviews have recently been devoted to
CBs is probably due to the fact that many CB associated processes
CB functions in RNA metabolism and RNP biogenesis in both ani-
can also occur in the nucleoplasm in the absence of CBs.12 It is
mal22-25 and plant cells,19 this review will cover these aspects briefly
thought that CBs can act as docking stations for a plethora of differ-
and will instead focus on non-conventional roles of CBs with par-
ent enzymes and substrates, effectively bringing together diverse
ticular emphasis on stress responses in plants.
cellular components in an organized manner to act as factories for
enhancing the speed of individual processes;13 a function which
may be absolutely essential for embryogenesis in mice and zebra-
Composition of Cajal bodies
fish, but not for some other activities.
It should also be noted that these processes in CBs may be Given their multifunctional character it is not surprising that
tightly regulated by diverse developmental and environmental CBs comprise a broad variety of structurally and functionally

CONTACT Michael E. Taliansky Michael.Taliansky@hutton.ac.uk Cell and Molecular Sciences, James Hutton Institute, Invergowrie, DD2 5DA, Dundee, UK.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis Group, LLC
780 A. J. LOVE ET AL.

Figure 1. Confocal image of the N. benthamiana nucleus with CB, as visualized by ectopic Agrobacterium-mediated expression of 2 fluorescently labeled CB markers: U2B00
protein (CB marker) fused to green fluorescent protein (GFP, green) and fibrillarin (a nucleolar and CB marker) fused to red fluorescent protein (mRFP, magenta). The
merged image is presented on the right. No, nucleolus (shown by solid line), CB, Cajal body (shown by arrow); the nucleus is shown by dashed line. Scale bars, 5 mm.

diverse protein and RNA species (reviewed in25). In addition to
coilin, the most abundant signature protein, the CB proteome
includes proteins involved in formation of small nuclear RNPs
(snRNP) required for splicing of pre-mRNA [such as survival
of motor neuron (SMN) protein, Gemins, Sm], small nucleolar
RNPs (snoRNP) involved in maturation (methylation and
pseudouridylation) of rRNAs, tRNAs, snRNAs (e.g. fibrillarin)
and signaling [small ubiquitin-related modifier (1, SUMO-1);
poly(ADP ribose)polymerase (PARP) and poly (ADP-ribose)
glycohydrolase (PARG)]. CBs in plants also contain compo-
nents involved in RNA silencing (Dicer 3-like, AGO 4, Pol V,
RDR2). Many of these proteins are known to interact with
themselves or with other CB components, thus creating a
potentially dense network of interactions, which may hold the
entire structure together. CB proteins found so far in plants are
listed in Table 1.
Among RNA species found in CBs are various small non-
coding RNAs such as snRNAs, snoRNAs and small Cajal body-
specific RNAs (scaRNAs; which have functions similar to
Table 1. Protein components of plant Cajal bodies.
Role/Function Protein References
Major scaffolding Coilin
protein of CBs
SnRNP (maturation U2B00 Spliceosomal protein, 3
snoRNAs in RNA maturation). Remarkably, CBs in plant cells
may also comprise poly(A) RNAs, including mRNAs.26 Functional
activities of plant CB components are discussed in sections below.
Coilin and CB assembly
The major scaffold protein component of CBs is coilin, which is
essential for CB formation and function. It has previously been
demonstrated that knockout, knockdown or mutation of coilin
homologues in Drosophila,7 mice,2,10 zebrafish,11 Arabidopsis4
or Nicotiana spp21 can prevent CB formation. Analysis of coilin
from these different organisms has indicated that there is low
amino acid homology (in particular in the middle region; the
N- and C-termini are more conserved; see Fig. S1), but there is
similar domain organization (Fig. 2). For example, coilin from
different species typically contains 2 nuclear localization signals
and a putative nucleolar localization signal in the central part
of the protein.8,27-30 Other common domains among the differ-
ent coilins are an N-terminal globular domain, a C-terminal
putative Tudor-like structure abutting a disordered C-terminus,
and a highly disordered central domain.30 Analysis of an Arabi-
dopsis thaliana coilin found that it was able to bind RNA
strongly and non-specifically; activities ascribed by the 2 sets of
4
basic amino acids in the N-terminal region and a set in the dis-
ordered central region.30 These data are consistent with other

and splicing) component of U2snRNP studies, which show that mammalian coilin interacts with RNA
SMN Survival motor neuron 108
in vivo, effectively binding hundreds of small non-coding
protein: plant homolog
109
RNAs (snRNAs, snoRNAs and scaRNAs).31 This suggests that
Gemin 2
Sm 110 coilin has a broadly conserved dynamic regulatory function,
111
PHAX Phosphorylated
adaptor for RNA export
SnoRNP (maturation) Fibrillarin 20 -O-ribose 83,112

methyltransferase
113
Dyskerin Pseudouridine
synthase
68
Gene silencing Dicer-like 3 RNaseIII-like
enzyme
65
AGO 4 ARGONAUTE4
68
Pol V DNA-dependent RNA
polymerase V
RDR2 RNA-dependent RNA 68 Figure 2. Schematic representation of the functional domains of coilin from Arabi-
polymerase 2 dopsis thaliana. NOD, an N-terminal ordered domain which is suggested to be
Signaling/stress PARP Poly(ADP-ribose) S. Makarova, N. Petukhova responsible for self-association. IDD, an internal disordered domain encompassing
responses polymerase and N. Kalinina, 2 nuclear localization signals (NLS1 and NLS2). CTD, a C-terminal domain which
unpublished results contains a presumable Tudor-like structure. Amino acid positions are indicated
below.

which permits CBs to act as a cellular center of small RNA
metabolism.
Upon binding RNA it was found that the N-terminal globu-
lar domain of Atcoilin underwent a conformational change
which catalyzed multimerization into aggregates. This is consis-
tent with other reports which have found that the N-terminal
92 amino acid sequence of coilin is critical for CB assembly,
self-interaction, targeting to CBs, and de novo CB forma-
tion.27,32,33 It is thought that this process is also influenced by
10 residues of the most distal end of the C-terminus, which
may control N-terminus self-interaction, which may in turn
regulate coilin localization,34 CB formation and number.35
Possible mechanisms of coilin involvement in CB assembly
have recently been discussed in detail by Machyna et al.25,36
Briefly, the model suggests that CBs may be nucleated by tether-
ing different CB components, proteins or RNAs, to a specific site
(usually transcriptionally active region) inside the nucleus in a
stochastic manner.37-39 Presumably multiple types of RNA (such
as snRNAs, snoRNAs, and/or scaRNAs) arising from separate
genomic loci may act as distinct “seeds” for further nucleation of
CBs via association of specific sets of proteins for particular
RNA species. Thus a group of pre-CB components would be
formed as independent entities22,25 and later on assembled into
mature CBs by a bridging protein, most probably coilin. Indeed,
coilin can directly interact with many CB proteins and RNAs,
thereby acting as a molecular “glue” which brings numerous dis-
tinct pre-CB components together via numerous protein-protein
and/or protein-RNA interactions.22,25 It is known that the sym-
metrical dimethylation of several arginine residues and the phos-
phorylation state of coilin can control its capacity to bind other
CB proteins and RNAs, and this in turn is thought to influence
pre-CB seed coalescence and maintenance.40,41 This “multiseed-
ing” model fits well with the observation that upon coilin knock-
out or depletion, cells will lack canonical CBs but instead
contain several types of residual bodies.25
There are some other sub-nuclear bodies which resemble
CBs by shape, size, intra-nuclear location, and also share some
protein and RNA components. One of the key differences
between these bodies and CBs is dependence of assembly on
coilin. An example is the Histone locus body (HLB) which is
known to be involved in processing of histone pre-mRNAs.42
Coilin is present in a substantial portion of HLBs (though not
in all), but in contrast to CBs, HLBs are unaffected by coilin
depletion.7 Some other bodies may contain no coilin at all, but
share other CB components; for example in plants Dicing bod-
ies (or D-bodies) totally lack coilin, but contain other CB resi-
dents (e.g., SmD3/SmB). These bodies also comprise the
nuclear RNA-binding protein HYL1 and RNase III enzyme
DCL1 (Dicer-like 1) with important roles in production of
miRNAs, which can in turn regulate gene expression via gene
silencing mechanisms.43-45 It is not clear why different sub-
nuclear bodies contain the same components; they just may be
in different functional complexes, or shuttle between these
compartments. Thus, defining nuclear bodies based on the
presence of certain constituents seems to be difficult, since
many of them can be present in other types of organelles as
well. However, most researchers in the field would agree that
CBs are sub-nuclear compartments containing coilin, and coi-
lin is absolutely required for CB assembly and integrity.
RNA BIOLOGY 781
Apart from its structural role in the formation of CBs, new
important functions of coilin have recently been discovered
and are discussed in the sections below. Functional activities of
other proteins listed in Table 1 are also reviewed below.
CB functions in RNA metabolism and RNP biogenesis
snRNPs. One major process that is intrinsically linked to CBs is
formation of spliceosomal particles, snRNPs, which control pre-
mRNA splicing. Spliceosome formation begins with synthesis and
migration of major U snRNAs (such as U1, U2, U4 and U5) to
CBs for recruitment of the export factors (PHAX and CRM1),
which then transport snRNAs to the cytoplasm.46 In the cytosol,
snRNAs associate with Sm proteins arranged into heptameric
rings, and undergo hypermethylation of their 50 caps. Specificity
of the interaction between snRNAs and Sm proteins is controlled
by the SMN complex composed of the survival motor neuron pro-
tein (SMN) and Gemin proteins. The Sm and hypermethylation
modifications target the complex back into the nucleus via a
snRNP import receptor. An additional snRNA, U6, is also pro-
duced however it does not migrate to the cytosol, but instead it is
retained in the nucleus where it is modified by addition of a
monomethyl cap. It was reported by Beven et al.3 that in the nuclei
of Pisum sativum these macromolecular complexes became asso-
ciated with CBs, which is consistent with other later findings
which additionally suggest that this association mediates matura-
tion of snRNPs prior to their participation in pre-mRNA splicing
in the nucleoplasm.19 In this complex, scaRNAs (described in
more detail below) which contain CB localization signals47 guide
maturation by promoting the pseudouridylation and methylation
of snRNAs.48,49
snoRNAs and scaRNAs
Another major class of small RNAs found in CBs are snoRNAs and
scaRNAs that are related in structure and primarily guide chemical
modifications of other RNAs, mainly rRNAs, tRNAs and snRNAs
(reviewed in19,25). There are 2 main types of snoRNA, the C/D box
snoRNAs and the H/ACA box snoRNAs which have different
functions. The C/D box snoRNAs are associated with fibrillarin
(methyltransferase) and other additional proteins to form
snoRNPs which direct 20 -O- methylation of RNA targets. The H/
ACA box snoRNAs forms a complex with dyskerin (pseudouridine
synthase) which guides pseudouridylation of specific nucleotides.
scaRNAs are abundant in CBs, contain either or both of the boxes
together and modify spliceosomal snRNAs during their final matu-
ration inside the CBs (see above). In plants several putative scaR-
NAs were identified through library screening50 and these were
later cloned and found to localize specifically to CBs,51 indicating
common modification mechanisms among different species. These
modifications are thought to be typically confined to regions of the
snRNA important for interaction with pre-mRNAs, other snRNAs
or spliceosomal proteins.52 Such interactions with diverse compo-
nents culminate in the production of fully functional U2, U4/U6
and U4/U6-U5 snRNPs, which are finally liberated from the CB
for splicing in the nucleoplasm. Some of these complexes are disso-
ciated during the splicing process and these maybe retargeted to
the CB for regeneration.
782 A. J. LOVE ET AL.
Since both sno- and scaRNAs and their associated proteins
co-localize inside CBs, it was proposed that CBs might play a
role in maturation of this type of RNPs.
Telomerase
A telomere is a section of DNA at each end of a chromosome
that contains repetitive nucleotide sequences which stabilizes
and protects the end of the chromosome from fusion with other
chromosomes and inappropriate attack by DNA modifying
machinery. In plants and other organisms the telomere length
is preserved predominantly via the activity of telomerase, an
RNP-based enzyme which consists of telomerase RNA (TR),
telomerase reverse transcriptase and other associated proteins
(reviewed in19,25). It is thought that loss of activity of this
enzyme may constitute a mechanism of aging. In most organ-
isms the catalytic subunit of this complex (TERT) is encoded
by one gene, but in plants it is possible that multiple TERT var-
iants are expressed, as indicated by studies on the allotetraploid
Nicotiana tabacum (tobacco), where 3 gene variants are present
(reviewed in53). Plant TERTs possess multiple nuclear localiza-
tion/export signals which may explain their localization in the
nucleus and the nucleolus.53 It would be expected that in these
locations the TERTs would interact with various protein part-
ners to facilitate modulation of telomere length, however only
very few interactors (such as plant telomeric dsDNA binding
proteins and plant homologs of human telomeric ssDNA bind-
ing protein) have been elucidated in planta; this is in contrast
to yeast and mammalian interactome studies in which an abun-
dance of TERT interactors have been uncovered.53 Interest-
ingly, in invertebrates the TR which co-purifies and is closely
associated with the TERT, contains a specific CB-targeting
CAB box. In human cells, CB localization of TR is absolutely
essential for telomere maintenance (reviewed in25). While the
CAB box has not been reported in plant TRs, it has been shown
that Arabidopsis TR is able to interact with dyskerin which is
known to be a component of CBs. Thus, the challenge would
be to elucidate if the plant telomerase pathway includes CBs.
Although the maintenance of telomeres is predominantly car-
ried out by telomerase (an RNP-based enzyme responsible for telo-
mere length), in some organisms such as plants, there are
additional mechanisms such as telomerase independent alternative
telomere lengthening (ALT) and recombination dependent
machinery which can participate in this role.53 With some organ-
isms such as Arabidopsis, it was indicated that if there is a deficit in
telomerase, the other systems such as the ALT pathway can com-
pensate and elongate the telomeres. This study also suggested that
ALT mechanisms may play a role in early plant development.53
However, the role of the telomerase independent pathways are
poorly studied from the context of CBs/coilin in plants.
New plant-specific CB functions in RNA regulatory
pathways
Nonsense-mediated mRNA decay (NMD)
The NMD pathway is a quality control mechanism that recog-
nizes and degrades aberrant (truncated) mRNAs with a prema-
ture termination codon. Several lines of evidence demonstrate
that in plants NMD may occur in the nucleolus whereas in ani-
mals this process is associated with cytoplasmic processing
bodies.54 Firstly, it has been shown that Arabidopsis exon junc-
tion complex proteins accumulate in the nucleolus,55 suggesting
a role for the nucleolus in mRNA production. Secondly, the
plant nucleolus has been reported to contain mRNAs, including
properly spliced, aberrantly spliced, and single exon gene tran-
scripts. Aberrant mRNAs are significantly more abundant in
the nucleolus, while fully spliced products are more abundant
in the nucleoplasm.54 The majority of the aberrant transcripts
contain premature termination codons and exhibit characteris-
tics of NMD substrates.54 In addition, the NMD Up-frameshift
(UPF) factors, UPF2 and UPF3 are co-localized with a nucleo-
lar marker protein, fibrillarin, in the nucleolus, suggesting that
the Arabidopsis nucleolus may be involved in recognizing aber-
rant mRNAs and NMD.54 Finally, direct correlation between
the accumulation of increased levels of aberrant mRNAs in the
nucleolus and their turnover by NMD has been demonstrated
using upf mutants, which have been shown to be impaired in
NMD such that mRNAs that are normally turned over by
NMD accumulate in these mutants.56,57 Given that fibrillarin is
a component of CBs and CBs are often physically and function-
ally associated with the nucleolus, it has been suggested that
CBs might also be involved in some aspects of NMD.19 This
suggestion is supported by recent observations showing that
CBs contain poly(A) RNAs including mRNAs.26 However, fur-
ther research is required to explore if direct functional links
between the nucleolus and CBs really exist to provide a fully
operational NMD pathway.
Gene silencing
Several recent reports implicate CBs as also being involved in
modulation of plant gene expression via the biogenesis of micro-
RNA (miRNA) and small interfering RNA (siRNA). These RNA
species can trigger transcriptional and post transcriptional gene
silencing (TGS and PTGS, respectively) to control gene expres-
sion by affecting mRNA production or degradation (reviewed
in58,59). The mechanism of TGS and PTGS is typically induced
in response to the presence of aberrant mRNA structures (such
as double stranded RNA or RNA with hairpin loops for exam-
ple) which may arise from endogenous genes, virus infection or
introduced transgenes. When aberrant RNAs are present they
are typically converted into dsRNA (if not already) by eukaryotic
or viral RNA-dependent RNA polymerases (RDRPs),58,59 prior
to their cleavage into 21-24 nucleotide (nt) dsRNAs by distinct
Dicer or Dicer-like (for plants) enzymes.58,59 For PTGS, short
21/22 nt dsRNA fragments become single stranded (mature
siRNA and miRNA) and associate with ARGONAUTE proteins
(AGO) to form the RNA-induced silencing complex (RISC),
which targets mRNA species containing complementary sequen-
ces for degradation, impinging on the expression of these partic-
ular genes.58,59 In the case of siRNA, one specific mRNA target
is degraded, whereas complexes consisting of miRNA can have
multiple targets which can affect mRNA species of different
genes. With regard to TGS, it has been suggested that both 21
and 24 nt dsRNAs can associate with AGO proteins to target
chromatin-associated scaffold transcripts in a sequence specific
manner.60-62 The complexes which become attached to

chromatin subsequently recruit DRM proteins to methylate the
DNA at cytosine in CHH, CHG and CG sequence contexts.63,64
These methylation patterns interfere with transcription of the
target gene through various mechanisms.65
In Arabidopsis thaliana it has been shown that components
of the silencing machinery, such as AGO4 and Dicer-like 3 can
co-localize with CBs in the nucleus.43,66,67 Moreover it has been
demonstrated that the major component of RDRP Pol V, which
transcribes noncoding and intergenic sequences to modulate
heterochromatin formation and silencing of overlapping and
adjacent genes,68 co-localizes with AGO4 to CBs in Arabidop-
sis. RDRP2 which is essential for synthesis of siRNAs from
retro-elements and transposons, and short distance cell-cell
spread of the transgene silencing signal, has also been found
associated with CBs in plants.69 Taken together this body of
data is suggestive that CBs may operate as processing centers in
plants which generate RNA species involved in silencing.19 In
addition, it has been found that in an Arabidopsis coilin mutant
which has impaired production of CBs, there is significant
reduction of overall AGO4 protein levels, suggesting that CBs
(or coilin itself) may play a role in stabilizing AGO4 protein.67
Finally, coilin and dicer-like 3 double mutants have exhibited a
small decrease in DNA methylation beyond that seen in dicer-
like 3 single mutants, but has not decreased methylation to the
levels detected in ago 4.67 These data suggest that although CBs
and/or coilin itself, may be required for a fully functioning
DNA methylation system which controls TGS in Arabidopsis,
the function of CBs may still partially remain in the coilin
mutant. It is possible that if formation of CBs is disrupted, their
function in DNA methylation may still be fulfilled by other
sub-nuclear bodies, e.g. pre-CB structures which may be
formed by CB components even in the absence of coilin (coilin
is required only for gluing these structures into CBs, as dis-
cussed above).
Newly identified functions of plant CBs in responses to
stress and disease
Cells rapidly respond to stress in a variety of ways by altering
their metabolism either to activate survival pathways or to initi-
ate cell death or apoptotic mechanisms that eventually elimi-
nates damaged cells. Stress also often results in inhibition of
major nuclear processes (e.g., DNA replication and transcrip-
tion) and reorganization of nuclear structure and architec-
ture.18 The role of CBs in stress-sensing mechanisms in
mammalian cells has been discussed in detail by Boulon et al.18
and will therefore be complemented here by recent advances in
studies of plant CBs in the context of biotic and abiotic stresses.
Virus infections
Viruses can enter plants either through mechanical damage,
soil microbes or via feeding by nematode and insect vectors.
Following entry into cells, replication occurs, which precedes
local cell-to-cell and long distance movement of the virus
through the plant. Such movement requires virions or nucleic
acid/protein complexes to translocate into neighboring cells via
plasmodesmata, which are intercellular conduits which links
the cytoplasm of contiguous cells.70 Through local spread the
RNA BIOLOGY 783
virus eventually reaches phloem vessels, a vascular network
which transports photoassimilates and macromolecules
throughout the plant, facilitating systemic dissemination of the
virus through the plant.70,71 For viruses to actively invade
plants they have to subvert existing plant cell processes and
machinery for replication and dissemination, while counteract-
ing anti-pathogen defense systems.
The nucleolus plays a crucial role in the infection cycle of
numerous DNA and RNA-containing viruses (reviewed in72-74).
Since DNA viruses tend to replicate within the nucleus it is easier
to comprehend their associations with the nucleolus. RNA viruses
replicate mainly within the cytoplasm of host cells so it is unex-
pected for them to be targeted to this organelle. However, the inter-
actions with the nucleolus are thought to be a universal “pan-virus”
phenomenon (reviewed in72-74), such that plant viruses do not dif-
fer from other eukaryotic viruses in this regard.74 Much less is
known about virus interactions with CBs.
One plant virus that targets the nucleolus is groundnut
rosette virus [GRV, a single-stranded (ss) RNA virus belonging
to the family Umbravirus]. In contrast to most plant viruses,
umbraviruses do not form conventional virus particles as they
do not encode a coat protein (CP) which is often required by
viruses to enable them to move systemically throughout their
host. However instead, GRV encodes the ORF3 protein which
compensates for the lack of conventional CP.75-78 This protein
shows no similarity to any viral or non-viral proteins (with the
exception of the corresponding proteins of other umbraviruses)
and acts as a long-distance movement protein which can bind
viral RNA to form filamentous RNP particles that protect the
RNA from degradation.76,77 These particles accumulate as
inclusions in the cytosol and are also thought to shuttle through
the phloem to distribute the viral genome throughout the
plant.76,78 In addition to the ORF3 protein localizing to cyto-
plasmic inclusions, it has also appeared to interact with nuclei
and is preferentially targeted to nucleoli.75,79
ORF3 localization to the nucleolus is thought to occur via inter-
action with reorganized multiple CB-like structures (CBLs) which
merge with the nucleolus (Fig. 3).80 The mechanisms by which
ORF3 targets to CBs and promotes the formation of CBLs remain
unelucidated, but likely involve ORF3 hijacking and subverting
existing CB transport and distribution pathways to control CB
form and function. For example, ORF3 may induce the redistribu-
tion of CB components (such as coilin, fibrillarin and U2B”)4 by
modulating the phosphorylation of coilin81,82 or the self-association
and interaction of CB and other nucleolar components.16,83 ORF3
eventually migrates from the nucleus to the cytoplasm, and during
this process it sequesters fibrillarin and deposits it in the cytosol, a
location where it is not normally found.80,84 It was hypothesized
that fibrillarin may contribute to the formation of cytoplasmic fila-
mentous ORF3 RNPs and the concomitant long-distance systemic
movement of these viral RNP complexes. Fibrillarin knockdown
experiments showed that fibrillarin is required for both these pro-
cesses, but not for the replication or local cell-to-cell spread of the
virus.80 In vitro work found that ORF3 can assemble into structures
similar to the filamentous viral RNPs formed in planta, when
mixed with fibrillarin and viral RNA; these structures were also
shown to be infectious.80,84 Formation of these assemblies requires
the interaction of the ORF3 leucine-rich region with the fibrillarin
GAR domain.80,85 It was later revealed from atomic force
784 A. J. LOVE ET AL.

Figure 3. Model of GRV infection. Upon GRV infection, the ORF3 protein enters the nucleus and is targeted to CBs, reorganizing them into multiple CB-like structures
(CBLs). The CBLs then move to and merge with the nucleolus via an unknown mechanism. Some host proteins are probably involved in targeting the ORF3 protein to the
CBs, reorganizing CBs and causing their fusion with the nucleolus. One such host protein is fibrillarin, which is eventually partially relocalized into the cytosol by the subse-
quent migration of the ORF3 protein to this destination. In the cytoplasm viral RNP complexes containing the ORF3 protein, fibrillarin and viral RNA form. When produced
in the companion cells of the phloem (a plant specific transport system used for trafficking assimilates and macromolecules), the viral RNPs migrate into the phloem sieve
elements (conducting cells) where they are transported to the rest of the plant to generate a systemic infection.

microscopy studies that the fibrillarin-ORF3 complexes form single main hallmark of RNA silencing) have not been shown to be
layer rings of 18-22 nm which encapsidate viral RNA to form a reduced in coilin KD plants. This indicates that silencing initia-
helical morphology.86 These structures, when formed in phloem tion is not inhibited in coilin deficient plants and that they are
companion cells, can enter sieve elements and move through the able to trigger specific silencing against TRV or BSMV at levels
plant to cause systemic infection. Thus, umbraviruses can hijack comparable with WT plants. Therefore it has been suggested
host rRNA and RNP processing machinery to perform unexpected that coilin/CBs may be involved in an unknown host defense
functions in unusual cellular locations to facilitate long distance mechanism operating in addition to RNA silencing.21
virus spread. However, the molecular mechanisms of these pro- While it seems that coilin/CB reduction may mediate plant
cesses remain unknown. One possibility involves the fact that fibril- defense responses to enhance infections by different viruses
larin can be post-translationally modified by asymmetric arginine species, the same study21 also reported the opposite phenome-
demethylation (reviewed in24). Arginine methylation often affects non, where coilin/CB KD were found to reduce symptom devel-
protein-protein interactions and impacts a variety of cellular pro- opment and accumulation of turnip vein clearing virus (TVCV;
cesses, such as protein trafficking and signal transduction87. Fur- ssRNA rod-shaped virus, tobamovirus; Fig. 4) and potato virus
ther research is necessary to elucidate if such modification is Y (PVY; ssRNA filamentous virus, potyvirus). Collectively these
associated with fibrillarin function in umbravirus movement. data suggest that coilin/CBs are important in regulating virus
In order to further understand the role of CBs in plant viral pathogenesis in plants. Although the underlying mechanisms
infection pathways, Shaw et al.21 knocked down (KD) coilin in
Nicotiana plants and found that this could differentially modu-
late plant responses to a diverse range of virus taxa. For exam-
ple, it was shown that coilin KD/CB depletion increases
accumulation of barley stripe mosaic virus (BSMV; ssRNA rod
shaped virus, hordeivirus) and tomato golden mosaic virus
(TGMV; DNA spherical virus, begomovirus) which may con-
comitantly enhance systemic virus spread. Interestingly, coilin/
CB deficiencies were also shown to impinge on recovery of
newly emergent leaves from symptoms induced by tomato
black ring virus (TBRV; ssRNA spherical virus, nepovirus) and
tobacco rattle virus (TRV; ssRNA rod shaped virus, tobravirus).
The recovery phenomenon occurs due to induction of silencing
mechanisms which attack viral genomes in new tissues; it was
thus intriguing that depletion of coilin/CBs could influence this
Figure 4. Example of symptoms induced by turnip vein-clearing virus in WT (left
process in the case of TBRV and TRV. However, in contrast to panel) and coilin KD (right panel) N. benthamiana plants. Images are courtesy of
expectations, the levels of TRV and BSMV specific siRNAs (the Dr J. Shaw (JHI).

remain to be elucidated, these observations suggest that there
might be interplay between coilin (and CB) activities and plant
antivirus defense. Disease outcome in virus infection is deter-
mined by the race between host defense and virus replication
and spread. Functions of coilin and /or CBs can presumably
contribute to either side in this race, implying that the mecha-
nisms involved are complex and interwoven.21 A possible activ-
ity of coilin may be to directly interact with viral proteins, as
was shown for virus proteins encoded by poa semilatent virus,
which is closely related to BSMV.88 Collectively these data sug-
gest that coilin (CBs) may have new functions that are either
exploited by plant viruses for their own benefit or are involved
in antivirus plant defense responses. These functions may also
be involved in other biological processes, such as stress
responses.
Abiotic stress
In mammalian cells, various types of both biotic and abiotic stress
often affect the nucleolus by inducing a complex range of changes
in its morphology, size and protein content.18,72 Moreover, proteo-
mic studies have uncovered a whole network comprising various
nucleolar proteins involved in stress responses.18,89-91 Altogether,
these findings suggest that the mammalian cell nucleolus can oper-
ate as a stress sensor and major hub for coordinating stress
responses.18,20 Given that CBs are physically and functionally asso-
ciated with the nucleolus, it is seems conceivable that CBs in con-
cert with the nucleolus, may play a role in stress sensing and
signaling pathways (reviewed in18). Indeed, different types of stress
such as UV irradiation, osmotic stress, transcriptional inhibition,
heat shock and starvation, alter structure of CBs and redistribute
coilin and other CB components.18
It has previously been reported that plant cells exposed to
high salt (NaCl), can induce osmotic shock, imbalance in the
cellular ion concentration and oxidative stress,92 which are
manifested by increased H2O2 production, accumulation of
programmed cell death (PCD) markers, cytosolic cytochrome c
leakage and bleaching.93,94 In order to determine whether coilin
Figure 5. Effect of coilin deficiency on salt stress responses in transgenic N. benthamiana plants. (A) Leaf disks were incubated in salt solution (250 mM NaCl) or water
over the course of 10 d at room temperature. KD, coilin knock down; WT, wild type. (B) Whole WT (left) and coilin KD (right) plants were watered with 300 mM NaCl solu-
tion over 10 d. Images are courtesy of Dr S.S. Makarova (Lomonosov Moscow State University).
RNA BIOLOGY 785
and/or CBs can influence such responses to abiotic stress, coilin
silenced KD transgenic or non-transgenic tobacco leaf discs
were treated with increased concentrations of NaCl. In the
non-transgenic discs, application of salt resulted in the loss of
their viability and pigmentation (bleaching) (Fig. 5A; S.
Makarova, N. Petukhova and N. Kalinina, unpublished results).
In contrast, with the coilin KD transgenic leaf discs, enhanced
viability (suppressed bleaching) of leaf discs and impaired
H2O2 accumulation was observed (Fig. 5A; S. Makarova, N.
Petukhova and N. Kalinina, unpublished results). The toxic
effect of salt stress at the whole-plant level was also consider-
ably attenuated in coilin KD plants (Fig. 5B; S. Makarova, N.
Petukhova and N. Kalinina, unpublished results). Taken
together this data could indicate that suppression of coilin gene
expression can confer salt tolerance. Stress signaling pathways
in plants comprise complex processes involving various mecha-
nisms, and CBs (or coilin) appear(s) to be a previously unrec-
ognized major player in these pathways. Thus, besides their
primary role in RNA metabolism and RNP biogenesis, CBs
may have additional functions in plant perception and
responses to stress.
Role of poly(ADP-ribose) polymerase (PARP)
New insights into molecular and cellular functions of CBs in
plant biotic (e.g., virus attack) and abiotic stress responses may
come from recent studies showing a close association of CBs
and the PARP family member, PARP1, in Drosophila cells.95
PARP1 is a nuclear protein which plays important roles in gen-
otoxic stress tolerance and DNA repair, transcription, cell cycle
control and cellular responses to biotic and abiotic stresses
including PCD-related processes.19,95-99 All these regulatory
functions can be achieved via the basic enzymatic activity of
PARP1, which is involved in post-translational modification of
specific proteins. PARP1 catalyzes the attachment of multiple
chains of ADP ribose [poly (ADP) ribose; PAR] from NAD to
target (acceptor) proteins, and the main acceptor is PARP1
protein itself.96,97 Interestingly, most of the PARP1 molecules
786 A. J. LOVE ET AL.
bind to chromatin and accumulate in the nucleolus. However,
upon automodification with PAR, PARP1 interacts with key
components of CBs, such as coilin and fibrillarin.95 This associ-
ation mediates the shuttling of the PARP1 and other PARylated
target proteins from chromatin and nucleolus into CBs for
recycling by PAR glycohydrolase (PARG) which hydrolyzes
PARylated proteins to free PAR or mono(ADP-ribose).95
Plant and mammalian PARPs have essentially similar struc-
tures suggesting that their enzymatic activities are conserved
across the plant and animal kingdoms.97 In plants, these activi-
ties have now been implicated in several physiological pro-
cesses, including responses to abiotic and biotic stresses.97 For
example, using RNAi approach it has been shown that PARP
suppression in Arabidopsis and Brassica napus (oilseed rape)
plants results in enhanced stress tolerance to drought, high
light and heat stress.100 Overexpressing PARP in soybean cells
is protective against low ROS concentrations, but exacerbated
cell death at high ROS concentrations.101 In addition, PARP
inhibitors protect soybean and tobacco cells from oxidative
stress and heat shock induced PCD.101,102
Poly(ADP-ribosyl)ation also has substantial impacts on
plant-pathogen interactions.
In particular, PARP knockout mutants of Arabidopsis have
been shown to exhibit enhanced susceptibility Pseudomonas
syringae pv. tomato (Pst) strain DC3000103 suggesting that
PARP is required for antibacterial resistance. Consistent with
this finding, PARP inhibitors have been reported to block certain
plant basal defense mechanisms including cell wall reinforcement
with callose and lignin, which are induced by microbe-associated
molecular patterns, such as bacterial flagellin or EF-Tu epito-
pes.104 Both callose deposition and fortification of cell walls with
lignin may be important factors in conferring resistance against
various plant pathogens.97 For example, callose deposition may
impose a direct physical barrier that restricts intercellular traf-
ficking of the virus through the plasmodesmata.105
Plant PARPs have also been implicated in differentiation
and cell cycle control pathways,97 which are known to overlap
with components of plant signaling in response to stresses.
Alterations in the poly(ADP-ribosyl)ation level induced by
extrinsic (biotic or environmental) or intrinsic (genetic/physio-
logical) cues play a central role in PARP-mediated cellular
stress and developmental signaling processes;96,97 however the
detailed molecular mechanisms underlying the these processes
remain largely uncharacterised. Given that the interaction of
PARP with coilin and fibrillarin seems to be a key factor in traf-
ficking the automodified PARP and other PARylated proteins
to CBs for recycling,95 it appears reasonable to hypothesize that
redistribution of coilin and fibrillarin as well as changes in CB
structure, number and content, induced by biotic/abiotic stress
or developmental factors, may directly modulate accumulation
and localization of PARP, target PARylated proteins and PAR.
It seems further conceivable that these factors trigger and prop-
agate multiple signals controlling various stress responses and
developmental processes. The corollary is that CBs (and their
components) may act as a stress sensor which can modify
PARP activity in order to activate various responses to biotic
and environmental stresses and developmental cues. It is thus
intriguing to speculate whether the coilin-mediated plant anti-
virus defense mechanisms described above are instigated by
modified PARP function, and also to what extent CB-PARP
interactions could control plant responses to other biotic and
abiotic stresses; potential pathways which warrant future
investigation.
Conclusions
Plant CBs like their animal counterparts, are distinct sub-
nuclear bodies involved in coordinating major processes of
RNA modification and RNP biogenesis. While the role and
mechanisms of CBs in influencing these processes have been
well elucidated, recent findings have indicated that CBs have
additional new cellular functions which remain largely
uncharacterized.
In particular, based on the functional and physical associa-
tion between the nucleolus and CBs it has been suggested that
plant CBs may take part in nonsense-mediated mRNA decay in
concert with the nucleolus. However, further research is
required to assess if NMD actually occurs in CBs and which
precise functions are associated with these sub-nuclear bodies.
Another RNA regulatory process which is often attributed to
plant CBs is gene silencing. Gene silencing refers to several mecha-
nistically related transcriptional and post-transcriptional pathways
which are involved in controlling and regulating gene expression.
It is becoming obvious that not all of them are affiliated with CBs.
In particular, our preliminary results have not found any direct
links between virus induced silencing and CB functions.21 An out-
standing question is therefore which silencing pathways are regu-
lated by CBs, and how CBs integrate these processes?
The results of the involvement of plant CBs in regulation of
plant responses to biotic and abiotic stresses are especially
intriguing, since they have provided a new tentative concept
hypothesizing that CBs may sense these stresses and activate
PARP-related processes to control them. There is remarkable
inter-kingdom functional conservation of PARP and CBs. Both
PARP and CBs have been implicated in responses to a wide
range of biotic and abiotic stresses. Furthermore, PARP is
known to be an important factor involved in the development
of defense responses to some human and animal viruses.106,107
Whether CBs operate as a mediator for sensing and triggering
PARP-activated systems for defense against these stresses in
different eukaryotic systems remains to be tested.
Plant CBs have also been implicated in virus-host interac-
tions, as the mechanistic properties of CBs may be hijacked by
some viruses for their own benefits. For example, it has been
shown that CB components, coilin and fibrillarin, can be used
by viruses to mediate virus replication and spread. Detailed
investigation of molecular mechanisms underlying these func-
tions will provide new insights into our understanding of sur-
prising multifunctional complexity of CBs.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Dr S.S. Makarova for communicating her unpublished results
and fruitful discussions.

Funding
This work was financially supported by Scottish Government Rural and
Environmental Science and Analytical Services Division (A.J.L., N.P. and
M.E.T.), the State Basic Research Program of China (2014CB138403; C.Y.,
J.C.) and the Royal Society – Russian Foundation for Basic Research (16-
54-10057-RS_a).
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