ATF4 degradation relies on a phosphorylation-dependent interaction with the SCFβTrCP ubiquitin ligase

The ubiquitin-proteasome pathway regulates gene expression through protein degradation. Here! we show that the F-box protein beta TrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for I kappaB alpha 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 beta TrCP. ATM ubiquitination in HeLa cells is enhanced in the presence of beta TrCP. The F-box-deleted beta 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 far the SCFbeta TrCP complex, which is the first mammalian E3 ubiquitin ligase identified so far for the control of the degradation of a bZIP transcription factor.