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      The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6.

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          Abstract

          Immune responses need to be tightly controlled to avoid excessive inflammation and prevent unwanted host damage. Here we report that germinal center kinase MST4 responded dynamically to bacterial infection and acted as a negative regulator of inflammation. We found that MST4 directly interacted with and phosphorylated the adaptor TRAF6 to prevent its oligomerization and autoubiquitination. Accordingly, MST4 did not inhibit lipopolysaccharide-induced cytokine production in Traf6(-/-) embryonic fibroblasts transfected to express a mutant form of TRAF6 that cannot be phosphorylated at positions 463 and 486 (with substitution of alanine for threonine at those positions). Upon developing septic shock, mice in which MST4 was knocked down showed exacerbated inflammation and reduced survival, whereas heterozygous deletion of Traf6 (Traf6(+/-)) alleviated such deleterious effects. Our findings reveal a mechanism by which TRAF6 is regulated and highlight a role for MST4 in limiting inflammatory responses.

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          Most cited references37

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          Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.

          TRAF6 is a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. We have purified a heterodimeric protein complex that links TRAF6 to IKK activation. Peptide mass fingerprinting analysis reveals that this complex is composed of the ubiquitin conjugating enzyme Ubc13 and the Ubc-like protein Uev1A. We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin. Blockade of this polyubiquitin chain synthesis, but not inhibition of the proteasome, prevents the activation of IKK by TRAF6. These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains.
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            Inferences, questions and possibilities in Toll-like receptor signalling.

            The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.
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              A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer.

              The Hippo pathway has been implicated in suppressing tissue overgrowth and tumor formation by restricting the oncogenic activity of YAP. However, transcriptional regulators that inhibit YAP activity have not been well studied. Here, we uncover clinical importance for VGLL4 in gastric cancer suppression and find that VGLL4 directly competes with YAP for binding TEADs. Importantly, VGLL4's tandem Tondu domains are not only essential but also sufficient for its inhibitory activity toward YAP. A peptide mimicking this function of VGLL4 potently suppressed tumor growth in vitro and in vivo. These findings suggest that disruption of YAP-TEADs interaction by a VGLL4-mimicking peptide may be a promising therapeutic strategy against YAP-driven human cancers. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nat. Immunol.
                Nature immunology
                1529-2916
                1529-2908
                Mar 2015
                : 16
                : 3
                Affiliations
                [1 ] National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
                [2 ] 1] State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China. [2] Peking University-Tsinghua University Joint Center for Life Sciences, Beijing, China.
                [3 ] 1] National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
                Article
                ni.3097
                10.1038/ni.3097
                25642822
                0a2bd779-b967-4764-9c6a-edc89e07f1be
                History

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