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

Newman, A. C., Kemp, A. J., Drabsch, Y., Behrends, C. and Wilkinson, S. (2017) Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins. Nature Communications, 8, 1537. (doi: 10.1038/s41467-017-00859-z) (PMID:29146913) (PMCID:PMC5691083)

Abstract

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.

• Item Type: Articles
• Additional Information: A.C.N. was funded by a Medical Research Council (UK) graduate studentship. This work was supported by Cancer Research UK in the form of a Career Development Fellowship to S.W. (C20685/A12825) and C.B. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Newman, Dr Alice and Wilkinson, Dr Simon
• Authors: Newman, A. C., Kemp, A. J., Drabsch, Y., Behrends, C., and Wilkinson, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Nature Communications 8: 1537
• Publisher Policy: Reproduced under a Creative Commons License