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      Hippo signaling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade

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          Abstract

          The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defense. The correlation between cellular nutrient/physical status and host antiviral defense is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 K63-linked ubiquitination and adaptors/substrates binding. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defense in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defense.

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          Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

          Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu … (2012)
          The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Triggering the interferon antiviral response through an IKK-related pathway.

            Sonia Sharma, Benjamin tenOever, Nathalie Grandvaux … (2003)
            Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.
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              Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.

              Ryan Udan, Madhuri Kango-Singh, Riitta Nolo … (2003)
              Proliferation and apoptosis must be precisely regulated to form organs with appropriate cell numbers and to avoid tumour growth. Here we show that Hippo (Hpo), the Drosophila homologue of the mammalian Ste20-like kinases, MST1/2, promotes proper termination of cell proliferation and stimulates apoptosis during development. hpo mutant tissues are larger than normal because mutant cells continue to proliferate beyond normal tissue size and are resistant to apoptotic stimuli that usually eliminate extra cells. Hpo negatively regulates expression of Cyclin E to restrict cell proliferation, downregulates the Drosophila inhibitor of apoptosis protein DIAP1, and induces the proapoptotic gene head involution defective (hid) to promote apoptosis. The mutant phenotypes of hpo are similar to those of warts (wts), which encodes a serine/threonine kinase of the myotonic dystrophy protein kinase family, and salvador (sav), which encodes a WW domain protein that binds to Wts. We find that Sav binds to a regulatory domain of Hpo that is essential for its function, indicating that Hpo acts together with Sav and Wts in a signalling module that coordinately regulates cell proliferation and apoptosis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 18 March 2017
                Publication date (Electronic): 27 March 2017
                Publication date (Print): April 2017
                Publication date PMC-release: 27 September 2017
                Volume: 19
                Issue: 4
                Pages: 362-374
                Affiliations
                [1 ]Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China
                [2 ]Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
                [3 ]Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
                [4 ]Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200031, China
                [5 ]Eye Center of the Second Affiliated Hospital School of Medicine, Institutes of Translational Medicine, Zhejiang University, Hangzhou, 310058, China
                [6 ]Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX77030, USA
                Author notes
                [8 ]Correspondence should be addressed to Pinglong Xu, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Nano Building, Room A555, Hangzhou, 310058, China, Tel: 86-571-88206078, xupl@ 123456zju.edu.cn
                [7]

                These two authors contribute equally;

                Article
                Manuscript ID: NIHMS855045
                DOI: 10.1038/ncb3496
                PMC ID: 5398908
                PubMed ID: 28346439
                SO-VID: f514c440-9b3b-4ece-b24e-f9cf35cedaed
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: hippo pathway,yap/taz,tbk1,antiviral response,host defense
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: hippo pathway, yap/taz, tbk1, antiviral response, host defense

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