HIGHLIGHTS

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | MARCH 2004 | 167

HIGHLIGHT ADVISORS

UELI AEBI

UNIVERSITY OF BASEL,SWITZERLAND

TOM L. BLUNDELL

UNIVERSITY OF CAMBRIDGE, UK

JOAN S. BRUGGE

HARVARD MEDICAL SCHOOL,BOSTON, MA, USA

PASCALE COSSART

INSTITUT PASTEUR, PARIS,FRANCE

PAMELA GANNON

CELL AND MOLECULARBIOLOGY ONLINE

SUSAN M. GASSER

UNIVERSITY OF GENEVA,SWITZERLAND

JEAN GRUENBERG

UNIVERSITY OF GENEVA,SWITZERLAND

ULRICH HARTL

MAX-PLANCK-INSTITUTE,MARTINSRIED, GERMANY

STEPHEN P. JACKSON

WELLCOME/CRC INSTITUTE,CAMBRIDGE, UK

WALTER NEUPERT

MUNICH UNIVERSITY, GERMANY

TONY PAWSON

SAMUEL LUNENFELD RESEARCHINSTITUTE, TORONTO, CANADA

NORBERT PERRIMON

HARVARD MEDICAL SCHOOL,BOSTON, MA, USA

THOMAS D. POLLARD

YALE UNIVERSITY, NEW HAVEN, CT, USA

JOHN C. REED

THE BURNHAM INSTITUTE, LA JOLLA, CA, USA

ANNE RIDLEY

LUDWIG INSTITUTE FOR CANCERRESEARCH, LONDON, UK

KAREN VOUSDEN

BEATSON INSTITUTE FOR CANCER RESEARCH, GLASGOW, UK

The stability of the proto-oncogenictranscription factor c-Jun is knownto be regulated by the ubiquitin–pro-teasome system, yet the identity of ac-Jun-specific ubiquitin ligase hasbeen elusive. Taking a leaf from plantbiology, Vishva Dixit and colleagueshave now identified a human ortho-logue of Arabidopsis thaliana de-eti-olated-1 (DET1), which regulatesphotomorphogenesis, and havefound that human DET1 promotesthe degradation of c-Jun by assem-bling a ubiquitin-ligase complex.

Dixit and colleagues found thattwo negative regulators of photo-morphogenesis in A. thaliana —DET1 and constitutively photomor-phogenic-1 (COP1) — are highlyconserved in mammals. Given thatDET1 and DNA-damage-bindingprotein-1 (DDB1) interact to regu-late photomorphogenesis, andDDB1 associates with cullin 4A(CUL4A) and regulator of cullins-1(ROC1) in mammalian ubiquitin-ligase complexes, the authorshypothesized that human DET1might also bind ubiquitin-ligasecomponents. This turned out to bethe case — tagged human DET1immunoprecipitated DDB1, CUL4A,ROC1 and COP1 .

A. thaliana COP1 provided a clueregarding the putative substrate(s) ofthis human multi-subunit ubiquitinligase, which the authors namedDCXhDET1–hCOP1. The plant COP1promotes the degradation of certain

basic-region–leucine-zipper (bZIP)transcription factors, and indeed,human COP1, as well as a prevalentsplice variant (COP1∆24), binds c-jun, JunB and JunD, but not othermembers of the Jun family of bZIPtranscription factors.

Next, Dixit and colleaguesanalysed DCXhDET1–hCOP1-subunitinteractions. In the absence ofDDB1, the association betweenCUL4A and DET1 was reduced,which indicates that DDB1 bridgesCUL4A and DET1. Similarly,decreasing DET1 expression reducedthe association between COP1 andDDB1 — so, DET1 links COP1 toDDB1, and thereby recruits c-Junto the DCXhDET1–hCOP1 complex.However, COP1∆24, which lackspart of the coiled-coil interactiondomain, did not bind DET1 and, as aresult, cannot associate withDCXhDET1–hCOP1. Furthermore, theauthors found that the COP1 RINGfinger is dispensable for c-Jun degra-dation, which implicates the ROC1RING finger as the functional ubiq-uitin-ligase domain of theDCXhDET1–hCOP1 complex.

To test the function of theDCXhDET1–hCOP1 complex, Dixit andco-workers treated cells that weretransfected with human DET1 andCOP1 with a proteasome inhibitor,and found that this blocked c-Jundegradation. Ubiquitylation of c-Jun was detected only when thecomplete complex was assembled;indeed, COP1∆24 did not promoteeffective ubiquitylation. Ablation ofany subunit of DCXhDET1–hCOP1 byRNA interference resulted inendogenous c-Jun accumulation —thereby confirming the physiologi-cal relevance of this c-Jun-specificubiquitin-ligase complex.

So, the authors conclude thathuman DET1 promotes the ubiqui-tylation and degradation of c-Junby promoting ubiquitin-ligase-complex assembly. And, comingback full circle to plants, given theconservation of the DCXhDET1–hCOP1

components, a similar ubiquitin-ligase complex might explain howA. thaliana DET1 and COP1 regu-late photomorphogenesis.

Arianne Heinrichs

References and linksORIGINAL RESEARCH PAPER Wertz, I. E. et al.Human de-etiolated-1 regulates c-Jun byassembling a CUL4A ubiquitin ligase. Science22 Jan 2004 (doi:10.1126/science.1093549)

Take a leaffrom plants

P R OT E I N D E G R A D AT I O N

© 2004 Nature Publishing Group