Phase separation of p62: roles and regulations in autophagy

Abstract

The phase separation of the cargo receptor sequestome-1/p62 (SQSTM1/p62) is a critical mechanism for assembling signaling complexes in autophagy. During this process, p62 undergoes phase separation upon binding to polyubiquitin chains, concentrating ubiquitinated substrates within p62 droplets. These droplets further gather membrane sources and core autophagy machineries to facilitate autophagosome formation. The dynamics of p62 droplets are finely tuned in response to autophagy signals triggered by cellular stresses. Recent studies have revealed new regulatory mechanisms that highlight the significance of p62 phase separation in regulating autophagy. This review summarizes and discusses the molecular mechanisms of p62 phase separation and its roles in autophagy, with particular emphasis on the regulation of p62 droplets and their interaction modes with autophagic membranes.

Keywords: cargo receptor; p62; p62 droplets; phase separation; selective autophagy.