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Autophagy, a regulated process vital for cellular homeostasis, can participate in defense against virus invasion. However, the relationship between poxviruses and host cell autophagy is not fully understood. This study shows that vaccinia virus (VACV) induces autophagy but blocks autophagosome-lysosome fusion. Modified vaccinia virus Ankara (MVA), an attenuated VACV strain that cannot replicate in most mammalian cells, fails to do so. Both pharmacological inhibition of early autophagy via 3-MA treatment and genetic ablation of ATG3 and ATG7 led to a significant enhancement of MVA replication. The VACV protein A52 inhibits autolysosome formation by disrupting interactions between SNAP29, STX17, and VAMP8, which is crucial for autophagic flux. Importantly, A52 also promotes the degradation of SNAP29, thereby aiding viral replication. Furthermore, SNAP29 is a newly identified host restriction factor for MVA, as its suppression enables MVA replication in human cells. These findings elucidate how poxviruses modulate autophagy for their own replication and further explain MVA\u2019s restriction in human cells.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014137","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:34:55Z","timestamp":1776101695000},"page":"e1014137","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Poxvirus A52 protein subverts autophagy flux by blocking autophagosome\u2013lysosome fusion to promote viral replication"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8677-9675","authenticated-orcid":true,"given":"Kang","family":"Niu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxiang","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junda","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baifen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxue","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6141-8775","authenticated-orcid":true,"given":"Chen","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"issue":"3","key":"ppat.1014137.ref001","doi-asserted-by":"crossref","first-page":"68","DOI":"10.15585\/mmwr.mm7203a4","article-title":"Epidemiology 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