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CRL4 AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling
Author(s) -
Chen SiHan,
Jang Gwendolyn M,
Hüttenhain Ruth,
Gordon David E,
Du Dan,
Newton Billy W,
Johnson Jeffrey R,
Hiatt Joseph,
Hultquist Judd F,
Johnson Tasha L,
Liu YiLiang,
Burton Lily A,
Ye Jordan,
Reichermeier Kurt M,
Stroud Robert M,
Marson Alexander,
Debnath Jayanta,
Gross John D,
Krogan Nevan J
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797508
Subject(s) - ubiquitin , ubiquitin ligase , cullin , cop9 signalosome , microbiology and biotechnology , ubiquitin protein ligases , adapter (computing) , biology , signal transducing adaptor protein , protein subunit , degron , signal transduction , biochemistry , enzyme , gene , protease , peptide hydrolases , electrical engineering , engineering
Multi‐subunit cullin‐ RING ligases ( CRL s) are the largest family of ubiquitin E3 ligases in humans. CRL activity is tightly regulated to prevent unintended substrate degradation or autocatalytic degradation of CRL subunits. Using a proteomics strategy, we discovered that CRL 4 AMBRA 1 ( CRL substrate receptor denoted in superscript) targets Elongin C ( ELOC ), the essential adapter protein of CRL 5 complexes, for polyubiquitination and degradation. We showed that the ubiquitin ligase function of CRL 4 AMBRA 1 is required to disrupt the assembly and attenuate the ligase activity of human CRL 5 SOCS 3 and HIV ‐1 CRL 5 VIF complexes as AMBRA 1 depletion leads to hyperactivation of both CRL 5 complexes. Moreover, CRL 4 AMBRA 1 modulates interleukin‐6/ STAT 3 signaling and HIV ‐1 infectivity that are regulated by CRL 5 SOCS 3 and CRL 5 VIF , respectively. Thus, by discovering a substrate of CRL 4 AMBRA 1 , ELOC , the shared adapter of CRL 5 ubiquitin ligases, we uncovered a novel CRL cross‐regulation pathway.