Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control.

Autophagy is a recycling mechanism involved in cellular homeostasis with key implications for health and disease. The conjugation of the ATG8 family proteins, which includes LC3B (also known as MAP1LC3B), to autophagosome membranes, constitutes a hallmark of the canonical autophagy process. After ATG8 proteins are conjugated to the autophagosome membranes via lipidation, they orchestrate a plethora of protein-protein interactions that support key steps of the autophagy process. These include binding to cargo receptors to allow cargo recruitment, association with proteins implicated in autophagosome transport and autophagosome-lysosome fusion. How these diverse and critical protein-protein interactions are regulated is still not well understood. Recent reports have highlighted crucial roles for post-translational modifications of ATG8 proteins in the regulation of ATG8 functions and the autophagy process. This Review summarizes the main post-translational regulatory events discovered to date to influence the autophagy process, mostly described in mammalian cells, including ubiquitylation, acetylation, lipidation and phosphorylation, as well as their known contributions to the autophagy process, physiology and disease.

LC3B phosphorylation regulates FYCO1 binding and directional transport of autophagosomes.

Macroautophagy (hereafter referred to as autophagy) is a conserved process that promotes cellular homeostasis through the degradation of cytosolic components, also known as cargo. During autophagy, cargo is sequestered into double-membrane vesicles called autophagosomes, which are predominantly transported in the retrograde direction to the perinuclear region to fuse with lysosomes, thus ensuring cargo degradation.1 The mechanisms regulating directional autophagosomal transport remain unclear. The ATG8 family of proteins associates with autophagosome membranes2 and plays key roles in autophagy, including the movement of autophagosomes. This is achieved via the association of ATG8 with adaptor proteins like FYCO1, involved in the anterograde transport of autophagosomes toward the cell periphery.1,3-5 We previously reported that phosphorylation of LC3B/ATG8 on threonine 50 (LC3B-T50) by the Hippo kinase STK4/MST1 is required for autophagy through unknown mechanisms.6 Here, we show that STK4-mediated phosphorylation of LC3B-T50 reduces the binding of FYCO1 to LC3B. In turn, impairment of LC3B-T50 phosphorylation decreases starvation-induced perinuclear positioning of autophagosomes as well as their colocalization with lysosomes. Moreover, a significantly higher number of LC3B-T50A-positive autophagosomes undergo aberrant anterograde movement to axonal tips in mammalian neurons and toward the periphery of mammalian cells. Our data support a role of a nutrient-sensitive STK4-LC3B-FYCO1 axis in the regulation of the directional transport of autophagosomes, a key step of the autophagy process, via the post-translational modification of LC3B.