Membrane Dynamics of Lysosomes

8/17/2019 Membrane Dynamics of Lysosomes

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Bhaskar Ganguly

Ph.D. , M.V.Sc., B.V.Sc. A.H.

MembraneDynamics of

Lysosomes


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INTRODUCTION

• Lysosomes were discovered by de Duve in 1949• Terminal degradative compartments of the endocytic

pathway•

~ 0.5 µm 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 6-phosphate receptors (MPRs); acid phosphatase is a

cytochemical marker


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LYSOSOMES AS DYNAMIC ORGANELLES

How are endocytosed macromolecules delivered to theLysosomes?


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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 biogenesisDirect fusion and formation of ‘hybrid organelle’

Discrimination between endosome and lysosome is based on MPRs


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“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 involvingcondensation of contents & removal of somemembrane proteins


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•

In some cells, lysosomes contain cell-type specificproteins, e.g. lytic granules in cytotoxic T cells & NKcells, dense granules of platelets, histamine containinggranules of basophils, & MHC-II and Antigen containing

MIICs in APCs (viz. macrophages, dendritic cells )• Secretory activity is regulated by Ca 2+• Activation of APC results in the emerging of tubules &

vesicles from MIICs to deliver peptide-MHC IIcomplexes to the cell surface


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Lysosomes as dynamic organelles (contd …) • Lysosomes are also involved in repair of damaged

plasma membrane• Repair of 1000 µm 2 plasma membrane of sea urchin egg

occurs within 5 sec; such eggs can be fertilized normally • Absolute requirement for Ca 2+ 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 contentof plasma membrane

• Dependent on Ca 2+ and Synaptotagmin VII• Trypanosoma cruzi stimulates lysosomes for creation of

site of entry


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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)


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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 bulkyhydrophobic a.a.

• Cytoplasmic di-leucine motifs are also used•

AP-3 is involved in direct traffic of LAMPs from TGN3. Autophagy

• Nutritionally starved cells are stimulated to form

autophagosome that fuses with lysosome


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MEMBRANE TRAFFIC OUT OF LYSOSOMES

• Reformation of lysosome from ‘hybrid organelle’ requires condensation of contents

• Also requires removal/ recycling of membrane proteins• Lumenal Ca 2+ & low pH are required for condensation;

inhibited by EGTA - AM (Ca2+ chelator) and bafilmycinA1 (ATPase inhibitor)

• Recycling of MPRs requires AP - 1, Rab 9 & TIP47 (tailinteracting protein - 47 kDa)

•

TIP47 is involved in cargo selection into recyclingvesicles• MPR recycling vesicles do not remove all other

‘removable’ proteins•

Other shuttling proteins are also involved


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Membrane Dynamics of Lysosomes