The coordination of membrane fission and fusion at the end of autophagosome maturation

Abstract

The two major objectives of macroautophagy are to sequester cargo away from the cytoplasm and deliver this material for breakdown in the lysosome. Sequestration is complete when the autophagosome membrane undergoes fission to produce separate inner and outer membranes, while delivery into the lysosome requires fusion of the outer autophagosome membrane with the lysosome membrane. Thus, the merging of membranes through fission and fusion underlies each of the pivotal events in macroautophagic clearance. How these merging events are controlled in the cell is poorly understood. Several recent studies however suggest that the two events may be temporally coordinated and rely upon members of the classic membrane fusion SNARE family as well as the autophagy-specific family of Atg8 proteins.

GABARAP Like-1 enrichment on membranes: Direct observation of trans-homo-oligomerization between membranes and curvature-dependent partitioning into membrane tubules

“…Furthermore, when Atg8-PE/LC3-PE numbers are reduced in the cytoplasm of yeast and various mammalian cell lines, the resulting autophagosomes are smaller and a larger proportion of intermediates remain open 10-12 , 13 , suggesting that Atg8-PE/LC3-PE is important in terminal membrane dynamics events like membrane elongation or pore closure. However, neither the lipidation event nor the mammalian Atg8 family is absolutely essential to the completion of autophagy [14][15][16] ; when the family is knocked out or lipidation is blocked, the autophagosomes that still form are delivered into the lysosome, but the efficiency and speed of closure and lysosome delivery are reduced (reviewed here 17 ). This suggests that these proteins do not play a central mechanistic role in autophagosome closure (for example these proteins are unlikely to be machines driving membrane fission or fusion 17,18 ) but instead are an auxiliary facilitator of membrane dynamics.…”

“…However, neither the lipidation event nor the mammalian Atg8 family is absolutely essential to the completion of autophagy [14][15][16] ; when the family is knocked out or lipidation is blocked, the autophagosomes that still form are delivered into the lysosome, but the efficiency and speed of closure and lysosome delivery are reduced (reviewed here 17 ). This suggests that these proteins do not play a central mechanistic role in autophagosome closure (for example these proteins are unlikely to be machines driving membrane fission or fusion 17,18 ) but instead are an auxiliary facilitator of membrane dynamics. The mechanism of their facilitation is still being established, but in other systems, facilitators often include proteins that scaffold the fusion machinery or participate in membrane tethering.…”

Imbalances in protein homeostasis caused by mutant desmin

“…The second major cellular system for the removal of misfolded and poly‐ubiquitinated proteins is the autophagy‐lysosome system . Our key findings in the analysis of macroautophagy were increased LC3B immunoreactivity, ultrastructural evidence of abundant autophagic vacuoles, and increased protein levels of the ULK1 initiator of and the SQSTM1/p62 receptor for autophagy in skeletal muscle tissue derived from homozygous R349P desmin knock‐in mice.…”

Regulation of anti-microbial autophagy by factors of the complement system

“…Autolysosomes represent the effective site of cargo degradation due to the catalytic microenvironment brought by the lysosomal vesicles [23,24,22,17]. Autophagosome maturation involves multiples factors of different classes including Rab GTPases, cytosqueleton proteins, soluble N-acetylmaleimidesensitive factor attachment protein receptors (SNARES), SYNTAXINs, membrane-tethering components of the homotypic fusion and vacuole protein sorting (HOPS) complex, endosomal sorting complexes required for transport (ESCRT) factors and the plekstrin homology domain containing adaptor PLEKHM1 [25]. The process is promoted by the BECLIN1-VPS34-VPS15-UVRAG complex (Class III PI3K complex II) and other factors including BIF-1.…”