Successful precise design of artificial ion channels

August 9, 2024

The sugar-mediated non-canonical ubiquitination impairs Nrf1, a transcription factor

The research group has recently discovered a novel glycan-mediated ubiquitination mechanism of glycoproteins, which plays a role in various physiological processes and diseases. Given that abnormalities in the ubiquitin–proteasome system are associated with numerous disorders, including age-related neurodegenerative diseases, this finding is expected to have broad impact from pathophysiology to fundamental biology.

Ubiquitinated proteins are typically degraded by the proteasome, a large proteolytic complex. The transcription factor Nrf1, which regulates proteasome expression, is a glycoprotein activated by the deglycosylating enzyme NGLY1. In NGLY1 deficient cells, Nrf1 is extensively ubiquitinated, and unexpectedly, it remains unusually stable, avoiding degradation. Based on this observation, the group uncovered a previously unknown glycan-dependent ubiquitination mechanism acting on Nrf1. This non-canonical ubiquitination involves the attachment of complex ubiquitin chains, which are resistant to deubiquitinating enzymes. The discovery of this Nrf1 inhibiting mechanism provides a basis for therapeutic strategies targeting diseases related to proteasome dysfunction.

 

Original article

Molecular Cell doi: 10.1016/j.molcel.2024.07.013

Y. Yoshida, T. Takahashi, N. Ishii, I. Matsuo, S. Takahashi, H. Inoue, A. Endo, H. Tsuchiya, M. Okada, C. Ando, T. Suzuki, N. Dohmae, Y. Saeki, K. Tanaka, T. Suzuki,

"Sugar-mediated non-canonical ubiquitination impairs Nrf1/NFE2L1 activation".

Contact

Naoshi Dohmae
Unit Leader
Biomolecular Characterization Unit