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The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit NEMO and directly engages the ubiquitin-dependent PINK1-Parkin pathway to induce mitophagy. Tax also recruits autophagy receptors NDP52 and p62\/SQSTM1 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires Parkin to limit the extent of cGAS-STING1 activation and suppress type I interferon (IFN) induction. HTLV-1-transformed T cell lines and PBMCs from HAM\/TSP patients exhibit hallmarks of chronic mitophagy, and inhibition of Parkin in HTLV-1-transformed cell lines downregulates p19 Gag expression and induces cell death. Collectively, our findings suggest that Tax manipulation of the PINK1-Parkin mitophagy pathway represents a new HTLV-1 immune evasion strategy important for maintaining viral gene expression and cell survival.<\/jats:p>","DOI":"10.1101\/2025.03.15.643451","type":"posted-content","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T16:55:23Z","timestamp":1742403323000},"source":"Crossref","is-referenced-by-count":1,"title":["HTLV-1 Tax induces PINK1-Parkin-dependent mitophagy to mitigate activation of the cGAS-STING1 pathway"],"prefix":"10.64898","author":[{"given":"Suchitra","family":"Mohanty","sequence":"first","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State College School of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujit","family":"Suklabaidya","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State College School of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelli","family":"Mnatsakanyan","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State College School of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward W.","family":"Harhaj","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State College School of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052304551074000_2025.03.15.643451v2.1","doi-asserted-by":"crossref","unstructured":"Gessain A , Cassar O . 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