CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling

被引：17

作者：

Chen, Si-Han ^{[1
,2
,3
,4
]}

Jang, Gwendolyn M. ^{[1
,3
,4
]}

Huttenhain, Ruth ^{[1
,3
,4
]}

Gordon, David E. ^{[1
,3
,4
]}

Du, Dan ^{[5
]}

Newton, Billy W. ^{[1
,3
,4
]}

Johnson, Jeffrey R. ^{[1
,3
,4
]}

Hiatt, Joseph ^{[6
,7
,8
,9
]}

Hultquist, Judd F. ^{[1
,3
,4
]}

Johnson, Tasha L. ^{[1
,3
,4
]}

Liu, Yi-Liang ^{[10
]}

Burton, Lily A. ^{[11
]}

Ye, Jordan ^{[12
,13
]}

Reichermeier, Kurt M. ^{[14
]}

Stroud, Robert M. ^{[3
,10
]}

Marson, Alexander ^{[3
,8
,9
,15
,16
,17
]}

Debnath, Jayanta ^{[12
,13
]}

Gross, John D. ^{[3
,11
]}

Krogan, Nevan J. ^{[1
,3
,4
,13
]}

机构：

[1] Univ Calif San Francisco, Calif Inst Quantitat Biosci, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Biophys Grad Program, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Quantitat Biosci Inst QBI, San Francisco, CA 94143 USA

[4] Gladstone Inst, San Francisco, CA USA

[5] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA

[10] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

[11] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA

[12] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA

[13] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[14] CALTECH, Pasadena, CA 91125 USA

[15] Univ Calif Berkeley, Div Infect Dis & Rheumatol, Berkeley, CA 94720 USA

[16] Univ Calif Berkeley, Innovat Genom Inst, Berkeley, CA 94720 USA

[17] Chan Zuckerberg Biohub, San Francisco, CA USA

来源：

EMBO JOURNAL | 2018年 / 37卷 / 18期

基金：

瑞士国家科学基金会;

关键词：

AMBRA1; cullin-RING ligase; HIV infection; interleukin-6; ubiquitin; F-BOX PROTEINS; SOCS-BOX; STRUCTURAL BASIS; HIV-1; VIF; IN-VIVO; REGULATES AUTOPHAGY; COP9; SIGNALOSOME; E3; LIGASES; COMPLEX; SUPPRESSOR;

D O I：

10.15252/embj.201797508

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Multi-subunit cullin-RING ligases (CRLs) 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 CRL4(AMBRA1) (CRL substrate receptor denoted in superscript) targets Elongin C (ELOC), the essential adapter protein of CRL5 complexes, for polyubiquitination and degradation. We showed that the ubiquitin ligase function of CRL4(AMBRA1) is required to disrupt the assembly and attenuate the ligase activity of human CRL5(SOCS3) and HIV-1 CRL5(VIF) complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4(AMBRA1) modulates interleukin-6/STAT3 signaling and HIV-1 infectivity that are regulated by CRL5(SOCS3) and CRL5(VIF), respectively. Thus, by discovering a substrate of CRL4(AMBRA1), ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross-regulation pathway.

引用

页数：22

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