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Review
. 2023 Aug:83:102190.
doi: 10.1016/j.ceb.2023.102190. Epub 2023 Jun 27.

Growing thin - How bulk lipid transport drives expansion of the autophagosome membrane but not of its lumen

Thomas James Melia  1
Affiliations
Review

Growing thin - How bulk lipid transport drives expansion of the autophagosome membrane but not of its lumen

Thomas James Melia. Curr Opin Cell Biol. 2023 Aug.

Abstract

The key event in macroautophagy is the de novo formation of a new organelle called the autophagosome which when complete, will have captured bits of cytoplasm within its double-membrane structure. Eventual fusion with the lysosome allows this captured material to be degraded back to simple molecules which can be recycled to support cell function during starvation. How autophagosomes form has been a challenging question for over 60 years. This review highlights work that forms the basis for an autophagosome membrane expansion model grounded in protein-mediated lipid transport.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:. Structural features of the forming autophagosome.
As the membrane gets bigger, the intralumenal separation of membranes gets smaller. Dimensions of the phagophore and autophagosome are taken from recent cryo-ET studies [1, 2] and are broadly consistent with various measurements from many other groups (reviewed in [52]). The seed vesicle has been contentious; Atg9 vesicles are quite small with dimensions approaching only 30 nm, while vesicles derived from other sources such as the COP-II machinery may be as big as 80 nm. Proto-phagophore represents an in between intermediate that may arise from vesicle fusion as in [47] or that appears in electron micrographs of cells where protein-mediated lipid transport is blocked [36, 37].
Figure 2:
Figure 2:. Putative Scramblase-Transporter-Scramblase Complex for bulk lipid transport.
ATG2 proteins bind tens of lipids and support bulk lipid transport [–15]. Under conditions where Atg2-mediated lipid transport is limiting for autophagosome growth, rates of lipid transport in yeast estimated at 200 lipids/sec/Atg2 [16]. ATG2 assembles with scramblases on the phagophore and the ER [–22], potentially creating a continuous channel to move lipids through the bilayers and through the contact site [24].
Figure 3:
Figure 3:. Lipid-transfer mediated membrane expansion model built upon ATG9 vesicle seeds.
Lipid transfer from the ER allows for a nearly unlimited supply of lipid. The seed membrane could be as little as a single ATG9 vesicle or a fusion of a few vesicles of different origins [36, 47]. ATG2 proteins stabilize the contact site, creating a pool of immobile autophagy protein enriched vesicles [3, 33]. As this vesicle membrane expands, additional soluble autophagy factors accumulate, including LC3-PE, but further addition of transmembrane proteins does not occur. Thus the ratio of ATG9 to LC3-PE goes down as autophagosomes grow [36].
See this image and copyright information in PMC

References

    1. Bieber A, et al., In situ structural analysis reveals membrane shape transitions during autophagosome formation. Proc Natl Acad Sci U S A, 2022. 119(39): p. e2209823119.

      *** Here, Wilfling, Baumeister and colleagues follow autophagosome formation in yeast using cryo-ET. Several highlights include describing the organization of the phagophore with respect to other cellular organelles, the capture of small and consistent morphologic changes indicative of the phagophore being pulled into contact sites, measurements of the changing intralumenal distance during phagophore growth, and a thoughtful discussion on the implications of membrane expansion without significant volume increases. In particular, they conclude that direct delivery of lipid must account for over 60% of all expansion and potentially for much more.

    1. Li M, et al., In situ snapshots along a mammalian selective autophagy pathway. Proc Natl Acad Sci U S A, 2023. 120(12): p. e2221712120. - PMC - PubMed
    1. Gomez-Sanchez R, et al., Atg9 establishes Atg2-dependent contact sites between the endoplasmic reticulum and phagophores. J Cell Biol, 2018. 217(8): p. 2743–2763. - PMC - PubMed
    1. Knorr RL, Dimova R, and Lipowsky R, Curvature of double-membrane organelles generated by changes in membrane size and composition. PLoS One, 2012. 7(3): p. e32753. - PMC - PubMed

    1. Agudo-Canalejo J and Knorr RL, Formation of Autophagosomes Coincides with Relaxation of Membrane Curvature. Methods Mol Biol, 2019. 1880: p. 173–188.

      *** Knorr and Mizushima build on previous work from their labs describing how “wetting” along a surface could explain much of the structures forming during membrane expansion. Here they tackle the problem of how autophagosomes capture bits of cytosol and of liquid-liquid like phase separated compartments. In addition to providing a surface along which the membrane can grow, they discuss how the energetics of membrane bending favor a cup-like structure which can mold into the phase-separated compartment.

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