TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages
Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activ...
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| Veröffentlicht in: | Cellular and molecular life sciences : CMLS 2021-03, Vol.78 (5), p.2315-2328 |
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| creator | Roh, Kyung-Hye Lee, Yeojin Yoon, Je-Hyun Lee, Danbi Kim, Eunju Park, Eunchong Lee, In Young Kim, Tae Sung Song, Hyun Kyu Shin, Jaekyoon Lim, Dae-Sik Choi, Eui-Ju |
| description | Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation. |
| doi_str_mv | 10.1007/s00018-020-03650-4 |
| format | Article |
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Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.</description><identifier>ISSN: 1420-682X</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-020-03650-4</identifier><identifier>PMID: 32975614</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Ablation ; Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Bone marrow ; Cell activation ; Cell Biology ; Cells, Cultured ; Cytokines ; Cytokines - blood ; Cytokines - genetics ; Cytokines - metabolism ; HEK293 Cells ; Humans ; Immune response ; Immune system ; Inflammation ; Kinases ; Life Sciences ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Macrophage Activation - drug effects ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - metabolism ; Mammals ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Negative feedback ; NF-kappa B - metabolism ; NF-κB protein ; Original ; Original Article ; Pattern recognition ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Protein-serine/threonine kinase ; Proteins ; Receptors ; Sepsis - blood ; Sepsis - genetics ; Sepsis - metabolism ; Septic shock ; Sequestosome-1 Protein - genetics ; Sequestosome-1 Protein - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Survival Analysis ; TLR4 protein ; TNF Receptor-Associated Factor 6 - genetics ; TNF Receptor-Associated Factor 6 - metabolism ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - metabolism ; Toll-like receptors ; TRAF6 protein ; Ubiquitination ; Ubiquitination - drug effects</subject><ispartof>Cellular and molecular life sciences : CMLS, 2021-03, Vol.78 (5), p.2315-2328</ispartof><rights>Springer Nature Switzerland AG 2020</rights><rights>Springer Nature Switzerland AG 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-a4b23520c0a9dec8b7f982a34a5e326fb93230c2876c2029126efaa93034c8a73</citedby><cites>FETCH-LOGICAL-c475t-a4b23520c0a9dec8b7f982a34a5e326fb93230c2876c2029126efaa93034c8a73</cites><orcidid>0000-0002-3642-0432</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11071754/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11071754/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32975614$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roh, Kyung-Hye</creatorcontrib><creatorcontrib>Lee, Yeojin</creatorcontrib><creatorcontrib>Yoon, Je-Hyun</creatorcontrib><creatorcontrib>Lee, Danbi</creatorcontrib><creatorcontrib>Kim, Eunju</creatorcontrib><creatorcontrib>Park, Eunchong</creatorcontrib><creatorcontrib>Lee, In Young</creatorcontrib><creatorcontrib>Kim, Tae Sung</creatorcontrib><creatorcontrib>Song, Hyun Kyu</creatorcontrib><creatorcontrib>Shin, Jaekyoon</creatorcontrib><creatorcontrib>Lim, Dae-Sik</creatorcontrib><creatorcontrib>Choi, Eui-Ju</creatorcontrib><title>TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.</description><subject>Ablation</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bone marrow</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Cytokines - blood</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophage Activation - drug effects</subject><subject>Macrophages</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Mammals</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Negative feedback</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Original</subject><subject>Original Article</subject><subject>Pattern recognition</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein-serine/threonine kinase</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Sepsis - blood</subject><subject>Sepsis - genetics</subject><subject>Sepsis - metabolism</subject><subject>Septic shock</subject><subject>Sequestosome-1 Protein - genetics</subject><subject>Sequestosome-1 Protein - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Survival Analysis</subject><subject>TLR4 protein</subject><subject>TNF Receptor-Associated Factor 6 - genetics</subject><subject>TNF Receptor-Associated Factor 6 - metabolism</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Toll-like receptors</subject><subject>TRAF6 protein</subject><subject>Ubiquitination</subject><subject>Ubiquitination - drug 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ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages</title><author>Roh, Kyung-Hye ; Lee, Yeojin ; Yoon, Je-Hyun ; Lee, Danbi ; Kim, Eunju ; Park, Eunchong ; Lee, In Young ; Kim, Tae Sung ; Song, Hyun Kyu ; Shin, Jaekyoon ; Lim, Dae-Sik ; Choi, Eui-Ju</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-a4b23520c0a9dec8b7f982a34a5e326fb93230c2876c2029126efaa93034c8a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Ablation</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bone marrow</topic><topic>Cell activation</topic><topic>Cell Biology</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Cytokines - blood</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophage Activation - drug effects</topic><topic>Macrophages</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Mammals</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Negative feedback</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Original</topic><topic>Original Article</topic><topic>Pattern recognition</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Protein-serine/threonine kinase</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Sepsis - blood</topic><topic>Sepsis - genetics</topic><topic>Sepsis - metabolism</topic><topic>Septic shock</topic><topic>Sequestosome-1 Protein - genetics</topic><topic>Sequestosome-1 Protein - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Survival Analysis</topic><topic>TLR4 protein</topic><topic>TNF Receptor-Associated Factor 6 - genetics</topic><topic>TNF Receptor-Associated Factor 6 - metabolism</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Toll-like receptors</topic><topic>TRAF6 protein</topic><topic>Ubiquitination</topic><topic>Ubiquitination - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Roh, Kyung-Hye</creatorcontrib><creatorcontrib>Lee, Yeojin</creatorcontrib><creatorcontrib>Yoon, Je-Hyun</creatorcontrib><creatorcontrib>Lee, Danbi</creatorcontrib><creatorcontrib>Kim, 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Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>78</volume><issue>5</issue><spage>2315</spage><epage>2328</epage><pages>2315-2328</pages><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>32975614</pmid><doi>10.1007/s00018-020-03650-4</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-3642-0432</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1420-682X |
| ispartof | Cellular and molecular life sciences : CMLS, 2021-03, Vol.78 (5), p.2315-2328 |
| issn | 1420-682X 1420-9071 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11071754 |
| source | MEDLINE; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | Ablation Animals Biochemistry Biomedical and Life Sciences Biomedicine Bone marrow Cell activation Cell Biology Cells, Cultured Cytokines Cytokines - blood Cytokines - genetics Cytokines - metabolism HEK293 Cells Humans Immune response Immune system Inflammation Kinases Life Sciences Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophage Activation - drug effects Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - metabolism Mammals Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Negative feedback NF-kappa B - metabolism NF-κB protein Original Original Article Pattern recognition Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Protein-serine/threonine kinase Proteins Receptors Sepsis - blood Sepsis - genetics Sepsis - metabolism Septic shock Sequestosome-1 Protein - genetics Sequestosome-1 Protein - metabolism Signal transduction Signal Transduction - drug effects Signaling Survival Analysis TLR4 protein TNF Receptor-Associated Factor 6 - genetics TNF Receptor-Associated Factor 6 - metabolism Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Toll-like receptors TRAF6 protein Ubiquitination Ubiquitination - drug effects |
| title | TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T13%3A41%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TRAF6-mediated%20ubiquitination%20of%20MST1/STK4%20attenuates%20the%20TLR4-NF-%CE%BAB%20signaling%20pathway%20in%20macrophages&rft.jtitle=Cellular%20and%20molecular%20life%20sciences%20:%20CMLS&rft.au=Roh,%20Kyung-Hye&rft.date=2021-03-01&rft.volume=78&rft.issue=5&rft.spage=2315&rft.epage=2328&rft.pages=2315-2328&rft.issn=1420-682X&rft.eissn=1420-9071&rft_id=info:doi/10.1007/s00018-020-03650-4&rft_dat=%3Cproquest_pubme%3E2501660298%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2501660298&rft_id=info:pmid/32975614&rfr_iscdi=true |