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Molecular and Cellular Biology, March 2001, p. 2192-2202, Vol. 21, No. 6
INSERM Unite 529, Interactions
Moléculaires
Hôte-pathogène1 and
CNRS, UPR 1524, Institut Cochin de Génétique
Moléculaire,2 75014 Paris,
France, and Department of Molecular and Cellular Biochemistry
and Neurobiotechnology Center, Ohio State University, Columbus,
Ohio3
Received 7 August 2000/Returned for modification 19 September
2000/Accepted 12 December 2000
The ubiquitin-proteasome pathway regulates gene expression through
protein degradation. Here we show that the F-box protein
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.6.2192-2202.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
ATF4 Degradation Relies on a
Phosphorylation-Dependent Interaction with the SCF
TrCP
Ubiquitin Ligase
TrCP, the
receptor component of the SCF E3 ubiquitin ligase responsible for
I
B
and
-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. Association between the two proteins depends on ATF4 phosphorylation and on ATF4 serine residue 219 present in the context of DSGXXXS, which is similar but not identical to the motif found in other substrates of
TrCP. ATF4 ubiquitination in HeLa cells is enhanced in the presence of
TrCP. The F-box-deleted
TrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated
transcription. ATF4 represents a novel substrate for the
SCF
TrCP complex, which is the first mammalian E3
ubiquitin ligase identified so far for the control of the degradation
of a bZIP transcription factor.
*
Corresponding author. Mailing address: INSERM Unite
529, ICGM, 24 rue de Faubourg Saint Jacques, 75014 Paris, France.
Phone: 33 1 44 41 25 65. Fax: 33 1 44 41 23 99. E-mail:
benarous{at}cochin.inserm.fr.
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