Proteostasis Governed by Autophagy and the UFM1 System

Host: Yogesh Kulathu

Venue: MSI Small Lecture Theatre, FLS

This seminar is funded by external sources

Abstract:

Proteostasis is safeguarded by multiple quality-control pathways, among which selective autophagy and the UFM1 system provide distinct yet complementary modes of regulation. In the first part of this talk, I will discuss how p62/SQSTM1-mediated selective autophagy is controlled through phosphorylation-dependent remodeling of p62 condensates. TBK1-mediated phosphorylation at Ser403 acts as a molecular rheostat that miniaturizes and gels p62 bodies, thereby enhancing their capacity to capture LC3-positive membranes and accelerate autophagic clearance of ubiquitinated proteins. This modification is counteracted by PP2A holoenzymes recruited via KEAP1. Phosphorylation-mimetic knock-in cells and mice accumulate compact, gel-like p62 condensates, demonstrating that this material-state switch operates across cellular and organismal levels to maintain proteostasis.

In the second part, I will present our findings on how proteostasis is further secured by a finely tuned cycle of UFM1 conjugation and deconjugation within the endoplasmic reticulum–associated ribosome quality-control (ER-RQC) pathway. The ER-anchored UFSP2–ODR4 complex functions as a spatially restricted UFMylation module for RPL26. Disruption of this module—or excessive UFM1 conjugation caused by biallelic UFC1 mutations—results in hyper-UFMylation, impaired ER-RQC, and neurodevelopmental defects. Together, these studies highlight how autophagy and the UFM1 system jointly govern neuronal proteostasis.

Bio:

Masaaki Komatsu, PhD, is Professor of Physiology at Juntendo University Graduate School of Medicine. His research focuses on the molecular mechanisms of selective autophagy and ubiquitin-like modification systems, particularly the regulation of p62/SQSTM1 condensates and the UFM1 pathway. He has contributed to the understanding of how autophagy maintains cellular proteostasis and protects against tissue injury and disease. His laboratory employs biochemical, structural, and in vivo approaches to elucidate the dynamic regulation of protein quality control.