Membrane targeting of core autophagy players during autophagosome biogenesis

Abstract

Autophagosomes are vital organelles required to facilitate the lysosomal degradation of cytoplasmic cargo, thereby playing an important role in maintaining cellular homeostasis. A number of autophagy-related (ATG) protein complexes are recruited to the site of autophagosome biogenesis where they act to facilitate membrane growth and maturation. Regulated recruitment of ATG complexes to autophagosomal membranes is essential for their autophagic activities and is required to ensure the efficient engulfment of cargo destined for lysosomal degradation. In this review, we discuss our current understanding of the spatiotemporal hierarchy between ATG proteins, examining the mechanisms underlying their recruitment to membranes. A particular focus is placed on the relevance of phosphatidylinositol 3-phosphate and the extent to which the core autophagy players are reliant on this lipid for their localisation to autophagic membranes. In addition, open questions and potential future research directions regarding the membrane recruitment and displacement of ATG proteins are discussed here.

The multifaceted functions of ATG16L1 in autophagy and related processes

“…Optimal kinase activity of ULK1 requires autophosphorylation and binding to its adaptor proteins, and acts to activate downstream factors including the VPS34 complex (Wong et al, 2013;Zachari and Ganley, 2017). The VPS34 complex, comprising the VPS34 lipid kinase, ATG14, Beclin-1 and VPS15 (also known as PIK3R4) (Itakura et al, 2008), catalyses the production of PI(3)P on the phagophore, which is essential for the recruitment of subsequent ATG players (including WIPI2, the ATG5 complex and ATG2 proteins) as well as for ATG8 lipidation (Dudley et al, 2020). The final stages of autophagy involve autophagosome maturation and closure, followed by lysosome fusion (forming the autolysosome) and require the lipidation of the ATG8 family members for their efficient execution (Johansen and Lamark, 2020;Nakamura and Yoshimori, 2017;Nguyen et al, 2016).…”

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

“…α‐Helices can anchor the protein to the membrane, ensuring its proper localisation and orientation [ 20 , 45 ]. Furthermore, amphipathic α‐helices can also function as sensors or modulators of the membrane curvature [ 46 ].…”

Rabaptin5 targets autophagy to damaged endosomes and SCVs by interaction with FIP200 and ATG16L1

“…Recently, it was also shown that the PI 3-kinase complex and WIPI2 mutually promote the recruitment of each other in a positive feedback loop (Fracchiolla et al, 2020). The many interactions between the components of the autophagy machinery reveal a complex network that goes beyond a linear chain of events in the development of autophagosomes (Dudley et al, 2020), but provides a degree of robustness and redundancy and may adapt to different cargos and targeting mechanisms.…”