Journal Article

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

Drabsch, Yvette, Kemp, Alain J., Behrends, Christian, Newman, Alice C., Wilkinson, Simon

2017

Overview

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 TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. 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-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ 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. Macroautophagy can regulate cell signalling and tumorigenesis but the molecular mechanisms are unclear. Here the authors show selective degradation of the signalling scaffold TRAF3 by autophagy and consequent activation of the NF-κB family member RELB regulate gene expression via antagonism of SMAD proteins.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/70 / 631/80/304 / 631/80/39/2346 / 631/80/86 / A549 Cells / Animals / Autophagy / Autophagy - genetics / Binding / Cancer / Cells, Cultured / Deoxyribonucleic acid / DNA / Female / Gene expression / Gene Expression Regulation, Neoplastic / Gene sequencing / HEK293 Cells / Humanities and Social Sciences / Humans / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Mice / Molecular modelling / multidisciplinary / NF-κB protein / Nucleotide sequence / Phagocytosis / Proteins / Proteomics / Regulatory sequences / RelB protein / Science / Science (multidisciplinary) / Signal transduction / Signaling / Smad protein / Smad Proteins - genetics / Smad Proteins - metabolism / Smad4 protein / TNF Receptor-Associated Factor 3 - genetics / TNF Receptor-Associated Factor 3 - metabolism / Transcription activation / Transcription Factor RelB - genetics / Transcription Factor RelB - metabolism / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Transplantation, Heterologous / Tumorigenesis / Tumorigenicity / Tumors