中央研究院 生物化學研究所

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 deUFMylation 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.

 * Keywords: Autophagy, p62, endoplasmic reticulum–associated ribosome quality-control, UFM1