Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins

作者：Newman Alice C; Kemp Alain J; Drabsch Yvette; Behrends Christian; Wilkinson Simon^*

来源：Nature Communications, 2017, 8(1): 1537.

DOI：10.1038/s41467-017-00859-z

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGF beta-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGF beta. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-kappa B family member RELB. We show that RELB represses TGF beta target promoters independently of DNA binding at NF-kappa B recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGF beta gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth.

• 出版日期2017-11-16