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Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins
Alice C Newman1,2, Alain J Kemp1, Yvette Drabsch1
1Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XR, UK.
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.
Insights
Macroautophagy, a cellular process, regulates tumor growth by controlling gene expression. This study reveals how ATG5-mediated autophagy impacts TGFβ signaling, affecting tumor development and providing insights into cancer mechanisms.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Macroautophagy's role in cell signaling and tumorigenesis is not fully understood.
- The specific molecular mechanisms by which autophagy regulates gene expression in cancer remain elusive.
Purpose of the Study:
- To elucidate the molecular mechanisms of autophagy in regulating tumorigenesis.
- To investigate the interplay between autophagy, TGFβ signaling, and RAS-driven cancers.
Main Methods:
- Established a RAS mutant cancer cell model (A549 cells) with varying ATG5 expression.
- Utilized proteomics to identify proteins selectively degraded by autophagy.
- Analyzed gene expression and protein-DNA interactions to understand pathway regulation.
Main Results:
- ATG5, while dispensable in vitro, promotes tumorigenesis in vivo.
- Autophagy selectively degrades TRAF3, leading to RELB activation.
- RELB represses TGFβ target gene expression by interacting with SMAD proteins, independent of canonical NF-κB binding.
Conclusions:
- Autophagy antagonizes TGFβ-mediated gene expression through TRAF3 degradation and RELB activation.
- Autophagy plays a crucial role in suppressing tumor growth by regulating gene expression.
- SMAD4 knockdown restores tumorigenicity in autophagy-deficient cells, highlighting autophagy's tumor-suppressive function.
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