Lassot I, Ségéral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F
INSERM Unite 529, Interactions Moléculaires Hôte-pathogène, 75014 Paris, France.
Mol Cell Biol. 2001 Mar;21(6):2192-202. doi: 10.1128/MCB.21.6.2192-2202.2001.
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.
泛素-蛋白酶体途径通过蛋白质降解来调节基因表达。我们在此表明，F-box蛋白βTrCP是负责IκBα和β-连环蛋白降解的SCF E3泛素连接酶的受体成分，它与ATF4（ATF-CREB bZIP转录因子家族的一员）在细胞核中共定位，并控制其稳定性。这两种蛋白质之间的关联取决于ATF4的磷酸化以及存在于DSGXXXS序列中的ATF4丝氨酸残基219，该序列与在βTrCP的其他底物中发现的基序相似但并不相同。在HeLa细胞中，βTrCP的存在会增强ATF4的泛素化。缺失F-box的βTrCP蛋白表现为负性反式显性突变体，可抑制ATF4的泛素化和降解，随后增强其在环磷酸腺苷介导的转录中的活性。ATF4是SCF(βTrCP)复合物的一种新底物，这是迄今为止鉴定出的首个负责控制bZIP转录因子降解的哺乳动物E3泛素连接酶。
