Membrane

Dynamics of
Lysosomes
Bhaskar Ganguly
Ph.D. , M.V.Sc., B.V.Sc. & A.H.

INTRODUCTION
Lysosomes were discovered by de Duve in 1949
Terminal degradative compartments of the endocytic
pathway
~ 0.5 m diameter; containing acid hydrolases
Membrane is rich in integral membrane glycoproteins
Lysosome associated membrane proteins (LAMPs)
Lysosome integral membrane proteins (LIMPs)
Lysosome glycoproteins (LGPs)

Differ from endosomes in the lack of Mannose 6phosphate receptors (MPRs); acid phosphatase is a
cytochemical marker

LYSOSOMES AS DYNAMIC ORGANELLES

How are endocytosed macromolecules delivered to the

Lysosomes?

Lysosomes as dynamic organelles (contd)

Models for Lysosomal Biogenesis

Maturation of late endosome to lysosome
Vesicular delivery from late endosome to lysosome
Kiss & Run hypothesis for lysosomal biogenesis
Direct fusion and formation of hybrid organelle
Discrimination between endosome and lysosome is based on MPRs

Lysosomes as dynamic organelles (contd)

Hybrid organelle hypothesis for lysosomal biogenesis

Studies on content mixing between late endosomes
and lysosomes in cell free assays
Formation of a hybrid organelle intermediate in density
to the two organelles
EM studies showed the hybrid organelle to contain
markers of each organelle
Hybrid organelle acts as site of hydrolysis; later,
lysosomes are reformed by a process involving
condensation of contents & removal of some
membrane proteins

Lysosomes as dynamic organelles (contd)

In some cells, lysosomes contain cell-type specific

proteins, e.g. lytic granules in cytotoxic T cells & NK
cells, dense granules of platelets, histamine containing
granules of basophils, & MHC-II and Antigen containing
MIICs in APCs (viz. macrophages, dendritic cells )
Secretory activity is regulated by Ca2+
Activation of APC results in the emerging of tubules &
vesicles from MIICs to deliver peptide-MHC II
complexes to the cell surface

Lysosomes as dynamic organelles (contd)

Lysosomes are also involved in repair of damaged

plasma membrane
Repair of 1000 m2 plasma membrane of sea urchin egg
occurs within 5 sec; such eggs can be fertilized normally
Absolute requirement for Ca2+ and yolk granules, which
are lysosome related organelles
Similar repair processes in many mammalian cells
Involves direct fusion of lysosomes with the plasma
membrane; characterized by increased LAMPs content
of plasma membrane
Dependent on Ca2+ and Synaptotagmin VII
Trypanosoma cruzi stimulates lysosomes for creation of
site of entry

MEMBRANE TRAFFIC INTO LYSOSOMES

1. Endocytic Pathway
Receptor mediated endocytosis (via clathrin coated
pits )
Non-clathrin mediated endocytic uptake

Phagocytosis
Caveolae mediated uptake
Macropinocytosis
Cholesterol sensitive uptake (carrying lipid rafts to Golgi
complex)

Membrane traffic into lysosomes (contd)

2. Biosynthetic Pathway
Newly synthesized integral membrane proteins are
delivered directly or indirectly through the TGN
Individual LAMPs take up different pathways
Lysosomal localization signal: Repeating (YXX#)
motif of 10-20 a.a.; X is any a.a., # is a bulky
hydrophobic a.a.
Cytoplasmic di-leucine motifs are also used
AP-3 is involved in direct traffic of LAMPs from TGN

3. Autophagy
Nutritionally starved cells are stimulated to form
autophagosome that fuses with lysosome

MEMBRANE TRAFFIC OUT OF LYSOSOMES

Reformation of lysosome from hybrid organelle
requires condensation of contents
Also requires removal/ recycling of membrane proteins
Lumenal Ca2+ & low pH are required for condensation;
inhibited by EGTA - AM (Ca2+ chelator) and bafilmycin
A1 (ATPase inhibitor)
Recycling of MPRs requires AP - 1, Rab 9 & TIP47 (tail
interacting protein - 47 kDa)
TIP47 is involved in cargo selection into recycling
vesicles
MPR recycling vesicles do not remove all other
removable proteins
Other shuttling proteins are also involved