Atg8ylation as a general membrane stress and remodeling response.

Suresh Kumar,Vojo Deretic,Jingyue Jia

doi:10.15698/cst2021.09.255

Abstract

The yeast Atg8 protein and its paralogs in mammals, mammalian Atg8s (mAtg8s), have been primarily appreciated for their participation in autophagy. However, lipidated mAtg8s, including the most frequently used autophagosomal membrane marker LC3B, are found on cellular membranes other than autophagosomes. Here we put forward a hypothesis that the lipidation of mAtg8s, termed ‘Atg8ylation', is a general membrane stress and remodeling response analogous to the role that ubiquitylation plays in tagging proteins. Ubiquitin and mAtg8s are related in sequence and structure, and the lipidation of mAtg8s occurs on its C-terminal glycine, akin to the C-terminal glycine of ubiquitin. Conceptually, we propose that mAtg8s and Atg8ylation are to membranes what ubiquitin and ubiquitylation are to proteins, and that, like ubiquitylation, Atg8ylation has a multitude of downstream effector outputs, one of which is autophagy.

Highlights

The yeast Atg8 protein and its seven mammalian Atg8 paralogs that include LC3A, LC3B, LC3B2, LC3C, GABARAP, GABARAPL1, and GABARAPL2/GATE16 [1,2,3] are best known for their role in autophagy [4], a process described early on along with the definition of lysosomes [5, 6]
We propose that mAtg8ylation is a cellular response that both counters membrane stress and is a mechanism involved in general membrane remodeling, with canonical autophagy being one manifestation
Atg8ylation may play additional roles in autophagy, for example as a modulator of the recruitment and/or function of SNAREs. This includes a large subset of Atg8 interacting motifs (AIM) (LIR)containing SNAREs including STX3, STX4, STX6, STX16, STX17, STX19, Vti1a, GOSR1, and VAMP7 [59,60,61], several of which are important in control of general membrane fusion and flow, as well as for autophagosomal [32], autolysosome [50], and lysosomal [61] biogenesis

Summary

Introduction

The yeast Atg8 protein and its seven mammalian Atg8 paralogs (mAtg8s) that include LC3A, LC3B, LC3B2, LC3C, GABARAP, GABARAPL1, and GABARAPL2/GATE16 [1,2,3] are best known for their role in autophagy [4], a process described early on along with the definition of lysosomes [5, 6]. Atg8ylation may play additional roles in autophagy, for example as a modulator of the recruitment and/or function of SNAREs. This includes a large subset of AIM (LIR)containing SNAREs including STX3, STX4, STX6, STX16, STX17, STX19, Vti1a, GOSR1, and VAMP7 [59,60,61], several of which are important in control of general membrane fusion and flow, as well as for autophagosomal [32], autolysosome [50], and lysosomal [61] biogenesis.

Results

Conclusion