A master conductor for aggregate clearance by autophagy

Abstract

Autophagic adapters including p62/SQSTM1 recognize polyubiquitinated targets such as toxic protein aggregates. In a recent issue of Molecular Cell, Filimonenko et al. provide evidence that the phosphatidylinositol 3-phosphate (PI3P) binding protein, Alfy, interacts with p62, Atg5, and PI3P to coordinate target recognition with site-specific activation of autophagic components.

Figure 1

Alfy and p62 cooperate in autophagosomal removal of protein aggregates. A. Binding interactions are denoted by blue dotted lines. Polyubiquitinated (Ub) protein aggregates are recognized by p62, an adapter that binds to LC3, a marquee autophagosomal protein. Alfy interacts with p62, Atg5, and PI3P. The Atg-12-Atg5-Atg16L complex bound to the WD40 domain of Alfy stimulates lipidation of LC3 to LC3-phospatidylethanolamine (LC3-PE). Alfy’s FYVE domain binds to PI3P on membranes that give rise to a nascent autophagosome. B. The interactions of Alfy, p62, LC3, other Atg factors, and PI3P-positive membranes lead to the formation of an autophagic phagophore that captures the toxic protein aggregate (e.g. polyQ-Huntingtin inclusion) for elimination in autolysosomes.