Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis

We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2021-05, Vol.206 (10), p.2420-2429
Main Authors: Occhigrossi, Luca, Rossin, Federica, D'Eletto, Manuela, Farrace, Maria Grazia, Ciccosanti, Fabiola, Petrone, Linda, Sacchi, Alessandra, Nardacci, Roberta, Falasca, Laura, Del Nonno, Franca, Palucci, Ivana, Smirnov, Evgeni, Barlev, Nick, Agrati, Chiara, Goletti, Delia, Delogu, Giovanni, Fimia, Gian Maria, Piacentini, Mauro
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33
cites cdi_FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33
container_end_page 2429
container_issue 10
container_start_page 2420
container_title The Journal of immunology (1950)
container_volume 206
creator Occhigrossi, Luca
Rossin, Federica
D'Eletto, Manuela
Farrace, Maria Grazia
Ciccosanti, Fabiola
Petrone, Linda
Sacchi, Alessandra
Nardacci, Roberta
Falasca, Laura
Del Nonno, Franca
Palucci, Ivana
Smirnov, Evgeni
Barlev, Nick
Agrati, Chiara
Goletti, Delia
Delogu, Giovanni
Fimia, Gian Maria
Piacentini, Mauro
description We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.
doi_str_mv 10.4049/jimmunol.2001122
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2522191436</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2522191436</sourcerecordid><originalsourceid>FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33</originalsourceid><addsrcrecordid>eNo9kM9PwjAUxxujEUTvnkyPXgavr13HjmgEF1ETmOel3Toc2Tpct0T-e0cAT9_D98fL-xByz2AsQISTbVFVna3LMQIwhnhBhsz3wZMS5CUZAiB6LJDBgNw4twUACSiuyYDzULA-NCTruFHWbcquVVVhlTMU6cpsulK1xtHI2l5pdLhStHuq9_S9zg5mYTe0_TZ0HUcfi0n89MYm0WrO6ey3cLfkKlelM3cnHZGv-Uv8_OotPxfR82zppQKC1hNcI2ipdIiB0nkOXGg_U9yAmjKRwZRLFYY-qmCq0e__MmEmA5-LLEsBFecj8njc3TX1T2dcm1SFS01ZKmvqziXoI7KQCS77KByjaVM715g82TVFpZp9wiA5oEzOKJMTyr7ycFrvdGWy_8KZHf8DhoRvYw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2522191436</pqid></control><display><type>article</type><title>Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis</title><source>EZB Electronic Journals Library</source><creator>Occhigrossi, Luca ; Rossin, Federica ; D'Eletto, Manuela ; Farrace, Maria Grazia ; Ciccosanti, Fabiola ; Petrone, Linda ; Sacchi, Alessandra ; Nardacci, Roberta ; Falasca, Laura ; Del Nonno, Franca ; Palucci, Ivana ; Smirnov, Evgeni ; Barlev, Nick ; Agrati, Chiara ; Goletti, Delia ; Delogu, Giovanni ; Fimia, Gian Maria ; Piacentini, Mauro</creator><creatorcontrib>Occhigrossi, Luca ; Rossin, Federica ; D'Eletto, Manuela ; Farrace, Maria Grazia ; Ciccosanti, Fabiola ; Petrone, Linda ; Sacchi, Alessandra ; Nardacci, Roberta ; Falasca, Laura ; Del Nonno, Franca ; Palucci, Ivana ; Smirnov, Evgeni ; Barlev, Nick ; Agrati, Chiara ; Goletti, Delia ; Delogu, Giovanni ; Fimia, Gian Maria ; Piacentini, Mauro</creatorcontrib><description>We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.2001122</identifier><identifier>PMID: 33941660</identifier><language>eng</language><publisher>United States</publisher><ispartof>The Journal of immunology (1950), 2021-05, Vol.206 (10), p.2420-2429</ispartof><rights>Copyright © 2021 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33</citedby><cites>FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33</cites><orcidid>0000-0002-1674-7091 ; 0000-0003-2106-1761 ; 0000-0001-6664-9257 ; 0000-0003-0481-6878 ; 0000-0003-0182-8267 ; 0000-0002-9209-1207 ; 0000-0001-8360-4376 ; 0000-0001-6987-920X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33941660$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Occhigrossi, Luca</creatorcontrib><creatorcontrib>Rossin, Federica</creatorcontrib><creatorcontrib>D'Eletto, Manuela</creatorcontrib><creatorcontrib>Farrace, Maria Grazia</creatorcontrib><creatorcontrib>Ciccosanti, Fabiola</creatorcontrib><creatorcontrib>Petrone, Linda</creatorcontrib><creatorcontrib>Sacchi, Alessandra</creatorcontrib><creatorcontrib>Nardacci, Roberta</creatorcontrib><creatorcontrib>Falasca, Laura</creatorcontrib><creatorcontrib>Del Nonno, Franca</creatorcontrib><creatorcontrib>Palucci, Ivana</creatorcontrib><creatorcontrib>Smirnov, Evgeni</creatorcontrib><creatorcontrib>Barlev, Nick</creatorcontrib><creatorcontrib>Agrati, Chiara</creatorcontrib><creatorcontrib>Goletti, Delia</creatorcontrib><creatorcontrib>Delogu, Giovanni</creatorcontrib><creatorcontrib>Fimia, Gian Maria</creatorcontrib><creatorcontrib>Piacentini, Mauro</creatorcontrib><title>Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.</description><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNo9kM9PwjAUxxujEUTvnkyPXgavr13HjmgEF1ETmOel3Toc2Tpct0T-e0cAT9_D98fL-xByz2AsQISTbVFVna3LMQIwhnhBhsz3wZMS5CUZAiB6LJDBgNw4twUACSiuyYDzULA-NCTruFHWbcquVVVhlTMU6cpsulK1xtHI2l5pdLhStHuq9_S9zg5mYTe0_TZ0HUcfi0n89MYm0WrO6ey3cLfkKlelM3cnHZGv-Uv8_OotPxfR82zppQKC1hNcI2ipdIiB0nkOXGg_U9yAmjKRwZRLFYY-qmCq0e__MmEmA5-LLEsBFecj8njc3TX1T2dcm1SFS01ZKmvqziXoI7KQCS77KByjaVM715g82TVFpZp9wiA5oEzOKJMTyr7ycFrvdGWy_8KZHf8DhoRvYw</recordid><startdate>20210515</startdate><enddate>20210515</enddate><creator>Occhigrossi, Luca</creator><creator>Rossin, Federica</creator><creator>D'Eletto, Manuela</creator><creator>Farrace, Maria Grazia</creator><creator>Ciccosanti, Fabiola</creator><creator>Petrone, Linda</creator><creator>Sacchi, Alessandra</creator><creator>Nardacci, Roberta</creator><creator>Falasca, Laura</creator><creator>Del Nonno, Franca</creator><creator>Palucci, Ivana</creator><creator>Smirnov, Evgeni</creator><creator>Barlev, Nick</creator><creator>Agrati, Chiara</creator><creator>Goletti, Delia</creator><creator>Delogu, Giovanni</creator><creator>Fimia, Gian Maria</creator><creator>Piacentini, Mauro</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1674-7091</orcidid><orcidid>https://orcid.org/0000-0003-2106-1761</orcidid><orcidid>https://orcid.org/0000-0001-6664-9257</orcidid><orcidid>https://orcid.org/0000-0003-0481-6878</orcidid><orcidid>https://orcid.org/0000-0003-0182-8267</orcidid><orcidid>https://orcid.org/0000-0002-9209-1207</orcidid><orcidid>https://orcid.org/0000-0001-8360-4376</orcidid><orcidid>https://orcid.org/0000-0001-6987-920X</orcidid></search><sort><creationdate>20210515</creationdate><title>Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis</title><author>Occhigrossi, Luca ; Rossin, Federica ; D'Eletto, Manuela ; Farrace, Maria Grazia ; Ciccosanti, Fabiola ; Petrone, Linda ; Sacchi, Alessandra ; Nardacci, Roberta ; Falasca, Laura ; Del Nonno, Franca ; Palucci, Ivana ; Smirnov, Evgeni ; Barlev, Nick ; Agrati, Chiara ; Goletti, Delia ; Delogu, Giovanni ; Fimia, Gian Maria ; Piacentini, Mauro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Occhigrossi, Luca</creatorcontrib><creatorcontrib>Rossin, Federica</creatorcontrib><creatorcontrib>D'Eletto, Manuela</creatorcontrib><creatorcontrib>Farrace, Maria Grazia</creatorcontrib><creatorcontrib>Ciccosanti, Fabiola</creatorcontrib><creatorcontrib>Petrone, Linda</creatorcontrib><creatorcontrib>Sacchi, Alessandra</creatorcontrib><creatorcontrib>Nardacci, Roberta</creatorcontrib><creatorcontrib>Falasca, Laura</creatorcontrib><creatorcontrib>Del Nonno, Franca</creatorcontrib><creatorcontrib>Palucci, Ivana</creatorcontrib><creatorcontrib>Smirnov, Evgeni</creatorcontrib><creatorcontrib>Barlev, Nick</creatorcontrib><creatorcontrib>Agrati, Chiara</creatorcontrib><creatorcontrib>Goletti, Delia</creatorcontrib><creatorcontrib>Delogu, Giovanni</creatorcontrib><creatorcontrib>Fimia, Gian Maria</creatorcontrib><creatorcontrib>Piacentini, Mauro</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Occhigrossi, Luca</au><au>Rossin, Federica</au><au>D'Eletto, Manuela</au><au>Farrace, Maria Grazia</au><au>Ciccosanti, Fabiola</au><au>Petrone, Linda</au><au>Sacchi, Alessandra</au><au>Nardacci, Roberta</au><au>Falasca, Laura</au><au>Del Nonno, Franca</au><au>Palucci, Ivana</au><au>Smirnov, Evgeni</au><au>Barlev, Nick</au><au>Agrati, Chiara</au><au>Goletti, Delia</au><au>Delogu, Giovanni</au><au>Fimia, Gian Maria</au><au>Piacentini, Mauro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2021-05-15</date><risdate>2021</risdate><volume>206</volume><issue>10</issue><spage>2420</spage><epage>2429</epage><pages>2420-2429</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-β production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNβ production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-β production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.</abstract><cop>United States</cop><pmid>33941660</pmid><doi>10.4049/jimmunol.2001122</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-1674-7091</orcidid><orcidid>https://orcid.org/0000-0003-2106-1761</orcidid><orcidid>https://orcid.org/0000-0001-6664-9257</orcidid><orcidid>https://orcid.org/0000-0003-0481-6878</orcidid><orcidid>https://orcid.org/0000-0003-0182-8267</orcidid><orcidid>https://orcid.org/0000-0002-9209-1207</orcidid><orcidid>https://orcid.org/0000-0001-8360-4376</orcidid><orcidid>https://orcid.org/0000-0001-6987-920X</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0022-1767
ispartof The Journal of immunology (1950), 2021-05, Vol.206 (10), p.2420-2429
issn 0022-1767
1550-6606
language eng
recordid cdi_proquest_miscellaneous_2522191436
source EZB Electronic Journals Library
title Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T17%3A34%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Transglutaminase%202%20Regulates%20Innate%20Immunity%20by%20Modulating%20the%20STING/TBK1/IRF3%20Axis&rft.jtitle=The%20Journal%20of%20immunology%20(1950)&rft.au=Occhigrossi,%20Luca&rft.date=2021-05-15&rft.volume=206&rft.issue=10&rft.spage=2420&rft.epage=2429&rft.pages=2420-2429&rft.issn=0022-1767&rft.eissn=1550-6606&rft_id=info:doi/10.4049/jimmunol.2001122&rft_dat=%3Cproquest_cross%3E2522191436%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c407t-43b20b6ab927abff034b5da3e0a814d0836a9952a78b25155e9d67534ddc02a33%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2522191436&rft_id=info:pmid/33941660&rfr_iscdi=true