Autophagosome maturation

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R-HSA-5682388
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Reaction [uncertain]
Species
Homo sapiens
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The mechanisms involved in the closure of the phagophore into an enclosed autophagosome are poorly understood. As the phagophore is a double-membraned structure, closure involves the fusion of a narrow opening, a process that is distinct from other membrane fusion events (Carlsson & Simonsen 2015). The topology of the phagophore is similar to that of multivesicular bodies (MVB) that form by invagination of the early endosome membrane, viral budding and cytokinesis. All of these rely on the Endosomal Sorting Complex Required for Transport (ESCRT) (Rusten et al. 2012). The ESCRT and associated proteins facilitate membrane budding away from the cytosol and subsequent cleavage of the bud neck (Hurley & Hanson 2010). Several studies have shown that depletion of ESCRT subunits or the regulatory ATPase Vps4, causes an accumulation of autophagosomes (Filimonenko et al. 2007, Lee et al. 2007, Rusten et al. 2007). Several ESCRT subunits are PI3P-binding proteins. PI3P turnover by phosphatases mediates dissociation of the early core ATGs from the phagophore membrane, appears to regulate autophagosome size and is required for closure of the phagophore to form an autophagosome (Taguchi-Atarashi et al. 2010), which suggests that ESCRTs are recruited to closing phagophores through interactions with PI3P and that PI3P levels are regulated to control phagophore closure (Carlsson & Simonsen 2015).

UVRAG is also involved in the maturation step, recruiting proteins that bring about membrane fusion such as the class C Vps proteins, which activate Rab7 thereby promoting fusion with late endosomes and lysosomes (Liang et al. 2008).

In yeast cells autophagosomes are formed at the single phagophore assembly site (PAS) next to the vacuole. In mammals, autophagosomes are formed at multiple locations in the cytoplasm and moved bidirectionally along microtubules with a bias towards the microtubule organising center (MTOC) where lysosomes are enriched. This transport requires the function of dynein motor proteins (Kimura et al. 2008). Depolymerization of microtubules or inhibition of dynein-dependent transport results in inhibition of autophagy (Kochl et al. 2006).

Literature References
PubMed ID Title Journal Year
25568151 Membrane dynamics in autophagosome biogenesis

Carlsson, SR, Simonsen, A

J. Cell. Sci. 2015
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