Dynamic Modulation of Exocyst Interaction Networks Integrates Hippo and mTOR Pathway Response to Pathogen Detection



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Monomeric RALGTPases, via direct binding to the exocyst (a.k.a Sec6/8 complex), help mount productive cell autonomous responses to trophic and immunogenic signals. However, RAL-exocyst downstream effectors register in a bewildering array of signaling events-- suggesting the presence of mechanisms that confer context dependent coordination amongst them. Here, we employed quantitative proteomics-based characterization of dynamic signal-dependent modulation of the exocyst interactome as an approach to detect such mechanisms. We identified sentinel innate immune kinases- PKR and TBK1 as host defense stimulus induced effectors of distinct exocyst subcomplexes specified by the presence of Exo84 versus Sec5 subunits. We find that, under virally compromised conditions, the Exo84 subcomplex accommodates Hippo signaling kinase MST1 together with PKR whereas a Sec5 subcomplex assists assembly of anabolic growth regulatory kinase mTOR together with TBK1. Detailed functional and biochemical analysis indicated that PKR directly phosphorylates MST1 for activation of Hippo signaling and consequent YAP1 inactivation. In parallel, TBK1 was found to be a positive regulator for mTOR and a negative regulator of YAP1 activity. Furthermore, RALB, which is activated by the host defense response, was found to be required and sufficient for induction of both Hippo and mTOR signaling through dual exocyst subcomplex engagement. RALB-dependent activation of these pathways can help cells deflect viral challenge and can be corrupted by oncogenes to help deflect apoptotic checkpoint activation. Thus, RAL-exocyst signaling complexes can be recognized as context-dependent mechanisms for integrated engagement of Hippo and mTOR signaling pathways.

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