Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation.
Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified ... CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional individual monoubiquitin modifications onto CRL client substrates. Our data define ARIH1 as a component of the human CRL system, demonstrate that ARIH1 can efficiently and specifically mediate monoubiquitylation of several CRL substrates, and establish principles for how two distinctive E3s can reciprocally control each other for simultaneous and joint regulation of substrate ubiquitylation. These studies have broad implications for CRL-dependent proteostasis and mechanisms of E3-mediated UB ligation.
Mesh Terms:
Carrier Proteins, Cullin Proteins, Gene Knockdown Techniques, HEK293 Cells, Humans, Mutation, NEDD8 Protein, Polyubiquitin, Proteomics, Substrate Specificity, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination, Ubiquitins
Carrier Proteins, Cullin Proteins, Gene Knockdown Techniques, HEK293 Cells, Humans, Mutation, NEDD8 Protein, Polyubiquitin, Proteomics, Substrate Specificity, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination, Ubiquitins
Cell
Date: Aug. 25, 2016
PubMed ID: 27565346
View in: Pubmed Google Scholar
Download Curated Data For This Publication
211511
Switch View:
- Interactions 124