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

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (5), p.109491-109491, Article 109491
• Main Authors: Zaman, Aubhishek, Wu, Xiaofeng, Lemoff, Andrew, Yadavalli, Sivaramakrishna, Lee, Jeon, Wang, Chensu, Cooper, Jonathan, McMillan, Elizabeth A., Yeaman, Charles, Mirzaei, Hamid, White, Michael A., Bivona, Trever G.
• Format: Article
• Language: English
• Subjects: Animals; autophagy; cancer cell survival; Cell Line, Tumor; Cell Survival; Cytosol - metabolism; eIF-2 Kinase - metabolism; exocyst; Hepatocyte Growth Factor - metabolism; Hippo pathway; Hippo Signaling Pathway; innate immune signaling; Mice; mTOR; Multiprotein Complexes - metabolism; Neoplasms - metabolism; Phosphorylation; PKR; Protein Binding; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; RAL; ral GTP-Binding Proteins - metabolism; TBK1; TOR Serine-Threonine Kinases - metabolism; virus; Virus Diseases - metabolism; Viruses - isolation & purification; YAP-Signaling Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109491

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. [Display omitted] •Exocyst protein subcomplexes impart phenotypic specificity•Exo84 exocyst contains PKR/MST1, activating Hippo signaling•Sec5 exocyst contains TBK1/mTOR, activating mTOR signaling•Cancer cells can coopt these subcomplexes for cellular survival Zaman et al. demonstrate that distinct exocyst subcomplexes modulate a RALB-mediated antiviral response. The authors identify PKR/MST1 interactions in an Exo84 subcomplex and TBK1/mTOR interactions in a Sec5 subcomplex, leading to engagement of Hippo and mTOR signaling, respectively, in pathogenic contexts, such as virus infection and cancer.