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How MPXV evades the host defense remain enigmatic. We performed expression screens and identified MPXV OPG147, a membrane fusion machinery protein, as an inhibitor of cGAS-MITA\/STING-mediated innate immunity. OPG147 from other poxviruses including the prototypic vaccinia virus (VACV) shows similar functions. OPG147 is associated with MITA\/STING and STIM1, a calcium sensor that retains MITA\/STING in the ER. OPG147 does not block cGAMP binding to MITA, but inhibits its ISGylation, dimerization\/oligomerization and trafficking, thereby suppressing its activation. Mutation of VACV OPG147 F55\/T116\/T117 to alanine (VACV\n                    <jats:sup>OPG147\/3A<\/jats:sup>\n                    ) has no effects on its infection and replication, but induces higher innate immune response compared with wild-type VACV in cells and mice. VACV\n                    <jats:sup>OPG147\/3A<\/jats:sup>\n                    infection also results in lower viral loads and decreased disease severity in mice. Our findings suggest that OPG147 contributes to immune evasion and is a virulence factor of poxviruses.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013198","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T14:01:12Z","timestamp":1749650472000},"page":"e1013198","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["The conserved poxvirus membrane entry-fusion apparatus component OPG147 targets MITA\/STING for immune evasion"],"prefix":"10.1371","volume":"21","author":[{"given":"Xue-Mei","family":"Yi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Yun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Han","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Qing","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Li","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Yu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hui","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Da","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9102-3272","authenticated-orcid":true,"given":"Hong-Bing","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"issue":"5","key":"ppat.1013198.ref001","doi-asserted-by":"crossref","first-page":"100185","DOI":"10.1016\/j.cellin.2024.100185","article-title":"The 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