Unique ubiquitination of Nrf1 (IMAGE)

Tokyo Metropolitan Institute of Medical Science

Unique ubiquitination of Nrf1

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Ubiquitin is a small protein consisting of 76 amino acids that binds to lysine residues of substrates, usually by a combination of three enzymes: a ubiquitin-activating enzyme (E1, two types), a ubiquitin-conjugating enzyme (E2, 40 types), and a ubiquitin ligase (E3, over 600 types). This reaction is repeated to form ubiquitin chains. This study found that the ubiquitination that inactivates Nrf1 was performed by two E3s (SCFFBS2-ARIH1) and one E2 (UBE2L3), which bind to the hydroxy groups of Ser and Thr near N-glycans and GlcNAc generated by the removal of N-type sugar chains by ENGASE. The ubiquitin chains formed were complex and branched. These atypical ubiquitin chains were resistant to deubiquitinating enzymes. Thus, in the absence of NGLY1, Nrf1 is detected as a stable ubiquitinated protein in the cytosol, and this ubiquitination prevents Nrf1 from nuclear transport.

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