p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy

Abstract

The degradation of misfolded proteins is essential for cellular homeostasis. Misfolded proteins are normally degraded by the ubiquitin-proteasome system (UPS), and selective autophagy serves as a backup mechanism when the UPS is overloaded. Selective autophagy mediates the degradation of harmful material by its sequestration within double-membrane organelles called autophagosomes. The selectivity of autophagic processes is mediated by cargo receptors, which link the cargo to the autophagosomal membrane. The p62 cargo receptor (SQSTM1) has a main function during the degradation of misfolded, ubiquitylated proteins by selective autophagy; here it functions to phase separate these proteins into larger condensates and tether them to the autophagosomal membrane. Recent work has given us crucial insights into the mechanism of action of the p62 cargo receptor during selective autophagy and how its activity can be integrated with the UPS. We will discuss these recent insights in the context of protein quality control and the emerging concept of cellular organization mediated by phase transitions.

Astragaloside-IV protects H9C2(2-1) cardiomyocytes from high glucose-induced injury via miR-34a-mediated autophagy pathway

“…P62, a ubiquitinbinding protein encoded by SQSTML on the autophagosome membrane, selectively recruits ubiquitin-binding proteins and binds to LC3 during autophagy, and transports them for autophagic degradation [29]. P62 markedly accumulates in autophagy-deficient cells, confirming that it is one of the marker proteins that reflect autophagy activity, and its content indirectly reflects the level of autophagosome clearance [30]. In addition, autophagy flow, briefly explained as the process of autophagy, becomes a new indicator to evaluate autophagy [31].…”

The Lysosome Pathway Degrades CD81 on the Cell Surface by Poly-ubiquitination and Clathrin-Mediated Endocytosis

“…Although MG132 is a well-known proteasome inhibitor, it also inhibits cathepsin K, a member of the lysosomal cathepsin family. 16) When 293T cells were exposed to these inhibitors, the amount of CD81 on the cell surface was comparable between DMSO-and lactacystin-treated cells. Bafilomycin A1, chloroquine, and MG132 increased CD81 expression compared to DMSO-and lactacystin-treatment.…”

Liquid–liquid phase separation in autophagy

“…The phase separation requires PB1 domain-mediated polymerization and the p62ubiquitin interaction and is modulated by the valency of the polyubiquitin chains and the p62-polyubiquitin chain binding affinity (Sun et al, 2018;Zaffagnini et al, 2018). p62 condensate formation is facilitated by increasing the binding affinity of p62, such as through phosphorylation of Ser 403 in the UBA domain, and it is attenuated by reducing the binding affinity of p62, such as through the M404T and G411S mutations in the UBA domain, which are found in Paget's disease of bone (Danieli and Martens, 2018;Sun et al, 2018;Zaffagnini et al, 2018). In condensates formed in vitro, p62 forms filaments that are cross-linked by polyubiquitin chains.…”