A lipid membrane-centric role of the SQSTM1/p62 body during autophagosome formation.

ABSTRACT

The phase separated SQSTM1/p62 body drives the formation of autophagosomes during macroautophagy/autophagy. However, the underlying mechanism by which the SQSTM1/p62 body acts during this process remains less understood. Recently, we reported that the SQSTM1/p62 body can work as a nucleation center to recruit local membrane sources for the expanding phagophore. Proteomics analysis reveals membrane vesicle-related components as important constituents of the SQSTM1/p62 body. ATG9- and ATG16L1-positive vesicles are recruited by the SQSTM1/p62 body as initial membrane sources of phagophores. ATG2 promotes the lipid transfer and vesicle fusion to further expand the membrane architecture of the initial phagophore. The lipid composition and content within the SQSTM1/p62 body is significantly affected by ATG2. The SQSTM1/p62 body also regulates the proper positioning and abundance of ATG9-positive vesicles. Furthermore, by spatially gathering ULK1 and membrane-anchored class III phosphatidylinositol (PtdIns) 3-kinase complexes, the SQSTM1/p62 body acts a local reaction platform to generate PtdIns-3-phosphate (PtdIns3P) to accelerate autophagosome maturation. These findings highlight a lipid membrane gathering model of the multifaceted SQSTM1/p62 body when driving autophagosome formation.