{"doi":"10.1101/2024.11.05.622030","title":"RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis needs to be better characterized. Here, we found that human RING1, but not RING2, promoted K48-linked ubiquitination of Gasdermin D (GSDMD) and acted as a negative regulator of pyroptosis and bacterial infection.\n                  <jats:italic>Ring1</jats:italic>\n                  knockout mice increased the bacterial loads and mortality rate by treatment of\n                  <jats:italic>S. typhimurium</jats:italic>\n                  . Upon infection by\n                  <jats:italic>M. tuberculosis</jats:italic>\n                  (Mtb) H37Rv strain, RING1 deletion initially reduced bacterial loads but later increased lung inflammation and impaired immune defense responses in mice. Also,\n                  <jats:italic>Ring1</jats:italic>\n                  knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS). Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by mutation or small molecular compound increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:caption>\n                      <jats:p>Graphic Abstract</jats:p>\n                    </jats:caption>\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"622030v1_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Highlights</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>E3 ubiquitin ligase RING1 targets GSDMD for proteasomal degradation.</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Mice lacking RING1 are more vulnerable to\n                        <jats:italic>S. typhimurium</jats:italic>\n                        infection and LPS- induced sepsis.\n                      </jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        In the early stages of\n                        <jats:italic>M. tuberculosis</jats:italic>\n                        (Mtb) infection,\n                        <jats:italic>\n                          Ring1\n                          <jats:sup>-/-</jats:sup>\n                        </jats:italic>\n                        mice exhibit efficient bacterial clearance.\n                      </jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Chronic inflammation in\n                        <jats:italic>\n                          Ring1\n                          <jats:sup>-/-</jats:sup>\n                        </jats:italic>\n                        mice impairs the ability to control Mtb in the late stages of infection.\n                      </jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>","journal":null,"year":null,"id":663677,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":523276,"name":"Wenqing Gao","orcid":"0009-0004-2222-7393","position":1,"is_corresponding":false},{"id":972889,"name":"Yuxin Qiu","orcid":"0009-0005-5938-9545","position":2,"is_corresponding":false},{"id":1732820,"name":"Jiasong Pan","orcid":null,"position":3,"is_corresponding":false},{"id":1213436,"name":"Qingqing Guo","orcid":"0000-0002-8951-6374","position":4,"is_corresponding":false},{"id":1732821,"name":"Xuehe Liu","orcid":null,"position":5,"is_corresponding":false},{"id":1732822,"name":"Lu Geng","orcid":null,"position":6,"is_corresponding":false},{"id":1732823,"name":"Yajie Shen","orcid":null,"position":7,"is_corresponding":false},{"id":639026,"name":"Zhidong Hu","orcid":"0000-0001-8490-4389","position":8,"is_corresponding":false},{"id":626411,"name":"Suhua Li","orcid":"0000-0001-5489-8643","position":9,"is_corresponding":false},{"id":931988,"name":"Shanshan Liu","orcid":"0000-0001-8367-6732","position":10,"is_corresponding":false},{"id":1010675,"name":"Hua Yang","orcid":"0000-0001-7514-7937","position":11,"is_corresponding":false},{"id":1732824,"name":"Baoxue Ge","orcid":null,"position":12,"is_corresponding":false},{"id":1732825,"name":"Xiaoyong Fan","orcid":null,"position":13,"is_corresponding":false},{"id":448965,"name":"Xiangjun Chen","orcid":"0000-0002-8108-9013","position":14,"is_corresponding":false},{"id":930714,"name":"Jixi Li","orcid":"0000-0003-3463-3175","position":15,"is_corresponding":false},{"id":656726,"name":"Yuanyuan Li","orcid":"0000-0002-1591-5815","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis needs to be better characterized. Here, we found that human RING1, but not RING2, promoted K48-linked ubiquitination of Gasdermin D (GSDMD) and acted as a negative regulator of pyroptosis and bacterial infection.\n                  <jats:italic>Ring1</jats:italic>\n                  knockout mice increased the bacterial loads and mortality rate by treatment of\n                  <jats:italic>S. typhimurium</jats:italic>\n                  . Upon infection by\n                  <jats:italic>M. tuberculosis</jats:italic>\n                  (Mtb) H37Rv strain, RING1 deletion initially reduced bacterial loads but later increased lung inflammation and impaired immune defense responses in mice. Also,\n                  <jats:italic>Ring1</jats:italic>\n                  knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS). Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by mutation or small molecular compound increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:caption>\n                      <jats:p>Graphic Abstract</jats:p>\n                    </jats:caption>\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"622030v1_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Highlights</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>E3 ubiquitin ligase RING1 targets GSDMD for proteasomal degradation.</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Mice lacking RING1 are more vulnerable to\n                        <jats:italic>S. typhimurium</jats:italic>\n                        infection and LPS- induced sepsis.\n                      </jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        In the early stages of\n                        <jats:italic>M. tuberculosis</jats:italic>\n                        (Mtb) infection,\n                        <jats:italic>\n                          Ring1\n                          <jats:sup>-/-</jats:sup>\n                        </jats:italic>\n                        mice exhibit efficient bacterial clearance.\n                      </jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Chronic inflammation in\n                        <jats:italic>\n                          Ring1\n                          <jats:sup>-/-</jats:sup>\n                        </jats:italic>\n                        mice impairs the ability to control Mtb in the late stages of infection.\n                      </jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":"https://openalex.org/W4404092862","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"green","license":"https://www.biorxiv.org/about/FAQ#license","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/11/06/2024.11.05.622030.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/11/06/2024.11.05.622030.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.11.05.622030","host_type":"publisher"},{"url":"https://doi.org/10.1101/2024.11.05.622030","host_type":"repository"}],"fields_of_study":["interferon and immune responses","Ubiquitin and proteasome pathways","RNA modifications and cancer"],"mesh_terms":[],"keywords":["Host response","Inflammatory response","Host (biology)","Pathogen","Biology","Inflammation","Immunology","Immune system","Ecology"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T23:01:48.808624Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}