ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.
The ubiquitin-proteasome pathway regulates gene expression through protein degradation. Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-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 betaTrCP. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. The F-box-deleted betaTrCP 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(betaTrCP) complex, which is the first mammalian E3 ubiquitin ligase identified so far for the control of the degradation of a bZIP transcription factor.
INSERM Unite 529, Interactions Moléculaires Hôte-pathogène, 75014 Paris, France.
I
I
Lassot
E
E
Ségéral
C
C
Berlioz-Torrent
H
H
Durand
L
L
Groussin
T
T
Hai
R
R
Benarous
F
F
Margottin-Goguet
D051701:Activating Transcription Factor 4; D020816:Amino Acid Motifs; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010453:Peptide Synthases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D044843:SKP Cullin F-Box Protein Ligases; D012694:Serine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D044844:beta-Transducin Repeat-Containing Proteins
C497109:ATF4 protein, human; C471644:BTRC protein, human; D014157:Transcription Factors; D044844:beta-Transducin Repeat-Containing Proteins; D051701:Activating Transcription Factor 4; D012694:Serine; D000242:Cyclic AMP; D044843:SKP Cullin F-Box Protein Ligases; D019204:GTP-Binding Proteins; D010453:Peptide Synthases