FIP200 Methylation by SETD2 Prevents Trim21-Induced Degradation and Preserves Autophagy Initiation

Abstract

FIP200, also known as RB1CC1, is a protein that assembles the autophagy initiation complex. Its post-translational modifications and degradation mechanisms are unclear. Upon autophagy activation, we find that FIP200 is methylated at lysine1133 (K1133) by methyltransferase SETD2. We identify the E3 ligase Trim21 to be responsible for FIP200 ubiquitination by targeting K1133, resulting in FIP200 degradation through the ubiquitin–proteasome system. SETD2-induced methylation blocks Trim21-mediated ubiquitination and degradation, preserving autophagy activity. SETD2 and Trim21 orchestrate FIP200 protein stability to achieve dynamic and precise control of autophagy flux.

SETD2 as an epigenetic sentinel of transcriptional fidelity in cardiomyocytes: a mechanistic link to heart failure

“…Recent investigations have identified FIP200, STAT1, and α-tubulin as non-histone targets of SETD2, implicating their role in regulating autophagy, interferon-mediated antiviral responses, and the formation of the mitotic spindle microtubular structure, respectively 32,33,60 . The involvement of SETD2mediated autophagy regulation appeared to be minimal, as no significant alterations were detected in the protein levels of FIP200 and LC3II in Setd2 KO hearts (Fig.…”