Mutant p53 suppresses innate immune signaling to promote tumorigenesis
Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of t...
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Veröffentlicht in: | Cancer cell 2021-04, Vol.39 (4), p.494-508.e5 |
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creator | Ghosh, Monisankar Saha, Suchandrima Bettke, Julie Nagar, Rachana Parrales, Alejandro Iwakuma, Tomoo van der Velden, Adrianus W.M. Martinez, Luis A. |
description | Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.
[Display omitted]
•Mutant p53 suppresses innate immune signaling and promotes immune evasion•Mutant p53 interacts with TBK1 to prevent STING-IRF3-TBK1 trimeric complex formation•Mutant p53 promotes tumor progression via cell-autonomous and non-autonomous signaling
Ghosh et al. show that mutant p53 suppresses downstream signaling from the cGAS/STING cytosolic DNA-sensing pathway by interacting with TANK-binding protein kinase 1 (TBK1), resulting in the attenuation of the type I interferon response and the promotion of tumor growth through immune evasion. |
doi_str_mv | 10.1016/j.ccell.2021.01.003 |
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[Display omitted]
•Mutant p53 suppresses innate immune signaling and promotes immune evasion•Mutant p53 interacts with TBK1 to prevent STING-IRF3-TBK1 trimeric complex formation•Mutant p53 promotes tumor progression via cell-autonomous and non-autonomous signaling
Ghosh et al. show that mutant p53 suppresses downstream signaling from the cGAS/STING cytosolic DNA-sensing pathway by interacting with TANK-binding protein kinase 1 (TBK1), resulting in the attenuation of the type I interferon response and the promotion of tumor growth through immune evasion.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2021.01.003</identifier><identifier>PMID: 33545063</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Carcinogenesis - immunology ; Carcinogenesis - metabolism ; Cell Transformation, Neoplastic - metabolism ; Cytosol - metabolism ; Gene Expression - genetics ; Gene Expression - immunology ; immune evasion ; Immunity, Innate - immunology ; innate immune signaling ; IRF3 ; Membrane Proteins - genetics ; Mice ; mutant p53 ; Nucleotidyltransferases - genetics ; Signal Transduction - immunology ; STING ; TBK1 ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - immunology</subject><ispartof>Cancer cell, 2021-04, Vol.39 (4), p.494-508.e5</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-2fb4bf763ebfed56ecc189c8a3baff7cda60a4eb4fc5092df9094f957751c13d3</citedby><cites>FETCH-LOGICAL-c459t-2fb4bf763ebfed56ecc189c8a3baff7cda60a4eb4fc5092df9094f957751c13d3</cites><orcidid>0000-0002-1288-5374</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccell.2021.01.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33545063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghosh, Monisankar</creatorcontrib><creatorcontrib>Saha, Suchandrima</creatorcontrib><creatorcontrib>Bettke, Julie</creatorcontrib><creatorcontrib>Nagar, Rachana</creatorcontrib><creatorcontrib>Parrales, Alejandro</creatorcontrib><creatorcontrib>Iwakuma, Tomoo</creatorcontrib><creatorcontrib>van der Velden, Adrianus W.M.</creatorcontrib><creatorcontrib>Martinez, Luis A.</creatorcontrib><title>Mutant p53 suppresses innate immune signaling to promote tumorigenesis</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.
[Display omitted]
•Mutant p53 suppresses innate immune signaling and promotes immune evasion•Mutant p53 interacts with TBK1 to prevent STING-IRF3-TBK1 trimeric complex formation•Mutant p53 promotes tumor progression via cell-autonomous and non-autonomous signaling
Ghosh et al. show that mutant p53 suppresses downstream signaling from the cGAS/STING cytosolic DNA-sensing pathway by interacting with TANK-binding protein kinase 1 (TBK1), resulting in the attenuation of the type I interferon response and the promotion of tumor growth through immune evasion.</description><subject>Animals</subject><subject>Carcinogenesis - immunology</subject><subject>Carcinogenesis - metabolism</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cytosol - metabolism</subject><subject>Gene Expression - genetics</subject><subject>Gene Expression - immunology</subject><subject>immune evasion</subject><subject>Immunity, Innate - immunology</subject><subject>innate immune signaling</subject><subject>IRF3</subject><subject>Membrane Proteins - genetics</subject><subject>Mice</subject><subject>mutant p53</subject><subject>Nucleotidyltransferases - genetics</subject><subject>Signal Transduction - immunology</subject><subject>STING</subject><subject>TBK1</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - immunology</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UV1L5TAQDYuyfuz-ggXpoy-9Js1H2wcFEb_AxRd9Dmk6uZtLm9QkFfz3pl4VfVkYmIE558xwDkJ_CF4RTMTJZqU1DMOqwhVZ4VyY_kD7pKmbkopG7OSZU14Kgps9dBDjBmcWqdufaI9SzjgWdB9d_Z2TcqmYOC3iPE0BYoRYWOdUgsKO4-ygiHbt1GDduki-mIIffd6lefTBrsFBtPEX2jVqiPD7vR-ix6vLh4ub8u7--vbi_K7UjLeprEzHOlMLCp2BngvQmjStbhTtlDG17pXAikHHjOa4rXrT4paZltc1J5rQnh6is63uNHcj9BpcCmqQU7CjCi_SKyu_b5z9J9f-WTaYMVzRLHD8LhD80wwxydHGxUblwM9RVqyps21MLFC6hergYwxgPs8QLJcE5Ea-JSCXBCTOhRfW0dcPPzkflmfA6RYA2adnC0FGbcFp6G0AnWTv7X8PvALsIJs2</recordid><startdate>20210412</startdate><enddate>20210412</enddate><creator>Ghosh, Monisankar</creator><creator>Saha, Suchandrima</creator><creator>Bettke, Julie</creator><creator>Nagar, Rachana</creator><creator>Parrales, Alejandro</creator><creator>Iwakuma, Tomoo</creator><creator>van der Velden, Adrianus W.M.</creator><creator>Martinez, Luis A.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1288-5374</orcidid></search><sort><creationdate>20210412</creationdate><title>Mutant p53 suppresses innate immune signaling to promote tumorigenesis</title><author>Ghosh, Monisankar ; Saha, Suchandrima ; Bettke, Julie ; Nagar, Rachana ; Parrales, Alejandro ; Iwakuma, Tomoo ; van der Velden, Adrianus W.M. ; Martinez, Luis A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-2fb4bf763ebfed56ecc189c8a3baff7cda60a4eb4fc5092df9094f957751c13d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Carcinogenesis - immunology</topic><topic>Carcinogenesis - metabolism</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cytosol - metabolism</topic><topic>Gene Expression - genetics</topic><topic>Gene Expression - immunology</topic><topic>immune evasion</topic><topic>Immunity, Innate - immunology</topic><topic>innate immune signaling</topic><topic>IRF3</topic><topic>Membrane Proteins - genetics</topic><topic>Mice</topic><topic>mutant p53</topic><topic>Nucleotidyltransferases - genetics</topic><topic>Signal Transduction - immunology</topic><topic>STING</topic><topic>TBK1</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghosh, Monisankar</creatorcontrib><creatorcontrib>Saha, Suchandrima</creatorcontrib><creatorcontrib>Bettke, Julie</creatorcontrib><creatorcontrib>Nagar, Rachana</creatorcontrib><creatorcontrib>Parrales, Alejandro</creatorcontrib><creatorcontrib>Iwakuma, Tomoo</creatorcontrib><creatorcontrib>van der Velden, Adrianus W.M.</creatorcontrib><creatorcontrib>Martinez, Luis A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghosh, Monisankar</au><au>Saha, Suchandrima</au><au>Bettke, Julie</au><au>Nagar, Rachana</au><au>Parrales, Alejandro</au><au>Iwakuma, Tomoo</au><au>van der Velden, Adrianus W.M.</au><au>Martinez, Luis A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutant p53 suppresses innate immune signaling to promote tumorigenesis</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2021-04-12</date><risdate>2021</risdate><volume>39</volume><issue>4</issue><spage>494</spage><epage>508.e5</epage><pages>494-508.e5</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.
[Display omitted]
•Mutant p53 suppresses innate immune signaling and promotes immune evasion•Mutant p53 interacts with TBK1 to prevent STING-IRF3-TBK1 trimeric complex formation•Mutant p53 promotes tumor progression via cell-autonomous and non-autonomous signaling
Ghosh et al. show that mutant p53 suppresses downstream signaling from the cGAS/STING cytosolic DNA-sensing pathway by interacting with TANK-binding protein kinase 1 (TBK1), resulting in the attenuation of the type I interferon response and the promotion of tumor growth through immune evasion.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33545063</pmid><doi>10.1016/j.ccell.2021.01.003</doi><orcidid>https://orcid.org/0000-0002-1288-5374</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Carcinogenesis - immunology Carcinogenesis - metabolism Cell Transformation, Neoplastic - metabolism Cytosol - metabolism Gene Expression - genetics Gene Expression - immunology immune evasion Immunity, Innate - immunology innate immune signaling IRF3 Membrane Proteins - genetics Mice mutant p53 Nucleotidyltransferases - genetics Signal Transduction - immunology STING TBK1 Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - immunology |
title | Mutant p53 suppresses innate immune signaling to promote tumorigenesis |
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