Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer

Aubhishek Zaman, Xiaofeng Wu, Andrew Lemoff, Sivaramakrishna Yadavalli, Jeon Lee, Chensu Wang, Jonathan Cooper, Elizabeth A. McMillan, Charles Yeaman, Hamid Mirzaei, Michael A. White, Trever G. Bivona

Research output: Contribution to journalArticlepeer-review

Abstract

The exocyst is an evolutionarily conserved protein complex that regulates vesicular trafficking and scaffolds signal transduction. Key upstream components of the exocyst include monomeric RAL GTPases, which help mount cell-autonomous responses to trophic and immunogenic signals. Here, we present a quantitative proteomics-based characterization of dynamic and signal-dependent exocyst protein interactomes. Under viral infection, an Exo84 exocyst subcomplex assembles the immune kinase Protein Kinase R (PKR) together with the Hippo kinase Macrophage Stimulating 1 (MST1). PKR phosphorylates MST1 to activate Hippo signaling and inactivate Yes Associated Protein 1 (YAP1). By contrast, a Sec5 exocyst subcomplex recruits another immune kinase, TANK binding kinase 1 (TBK1), which interacted with and activated mammalian target of rapamycin (mTOR). RALB was necessary and sufficient for induction of Hippo and mTOR signaling through parallel exocyst subcomplex engagement, supporting the cellular response to virus infection and oncogenic signaling. This study highlights RALB-exocyst signaling subcomplexes as mechanisms for the integrated engagement of Hippo and mTOR signaling in cells challenged by viral pathogens or oncogenic signaling.

Original languageEnglish (US)
Article number109491
JournalCell Reports
Volume36
Issue number5
DOIs
StatePublished - Aug 3 2021

Keywords

  • autophagy
  • cancer cell survival
  • exocyst
  • Hippo pathway
  • innate immune signaling
  • mTOR
  • PKR
  • RAL
  • TBK1
  • virus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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