{Reference Type}: Journal Article
{Title}: Sugar-mediated non-canonical ubiquitination impairs Nrf1/NFE2L1 activation.
{Author}: Yoshida Y;Takahashi T;Ishii N;Matsuo I;Takahashi S;Inoue H;Endo A;Tsuchiya H;Okada M;Ando C;Suzuki T;Dohmae N;Saeki Y;Tanaka K;Suzuki T;
{Journal}: Mol Cell
{Volume}: 84
{Issue}: 16
{Year}: 2024 Aug 22
{Factor}: 19.328
{DOI}: 10.1016/j.molcel.2024.07.013
{Abstract}: Proteasome is essential for cell survival, and proteasome inhibition induces proteasomal gene transcription via the activated endoplasmic-reticulum-associated transcription factor nuclear factor erythroid 2-like 1 (Nrf1/NFE2L1). Nrf1 activation requires proteolytic cleavage by DDI2 and N-glycan removal by NGLY1. We previously showed that Nrf1 ubiquitination by SKP1-CUL1-F-box (SCF)FBS2/FBXO6, an N-glycan-recognizing E3 ubiquitin ligase, impairs its activation, although the molecular mechanism remained elusive. Here, we show that SCFFBS2 cooperates with the RING-between-RING (RBR)-type E3 ligase ARIH1 to ubiquitinate Nrf1 through oxyester bonds in human cells. Endo-β-N-acetylglucosaminidase (ENGASE) generates asparagine-linked N-acetyl glucosamine (N-GlcNAc) residues from N-glycans, and N-GlcNAc residues on Nrf1 served as acceptor sites for SCFFBS2-ARIH1-mediated ubiquitination. We reconstituted the polyubiquitination of N-GlcNAc and serine/threonine residues on glycopeptides and found that the RBR-specific E2 enzyme UBE2L3 is required for the assembly of atypical ubiquitin chains on Nrf1. The atypical ubiquitin chains inhibited DDI2-mediated activation. The present results identify an unconventional ubiquitination pathway that inhibits Nrf1 activation.