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The HTLV-1 accessory protein p8 is cleaved from its precursor p12, and both proteins are required for viral persistence. Moreover, p8 enhances viral infectivity by inducing cell-cell contacts and cellular conduit formation. To date, host factors cleaving p12 to p8 remain unknown. Here, we report that p12 carries a signal peptide that is cleaved by the signal peptidase complex (SPC) to generate p8, and blocking of p12 cleavage correlated with a decreased cell aggregation and conduit formation, leading to impaired viral transmission of chronically HTLV-1 infected MT-2 cells. Bioinformatics identified p12 to carry a signal peptide, which is cleaved to generate p8. Inhibition of the SPC function by the SPC-specific inhibitor Cavinafungin and transient knockdown of SPC subunits confirmed the importance of the SPC to cleave p12 to p8. Mutational studies of the signal peptide sequence based on bioinformatics predictions generated cleavage-deficient p12 mutants and verified critical residues for signal peptide cleavage. Further, co-culture assays between Cavinafungin pre-treated chronically infected MT-2 cells, which transmit HTLV-1 dependent on p8, and Jurkat T-cells revealed a significantly impaired viral cell-cell transmission, suggesting that blockage of p12 cleavage interferes with p8-dependent HTLV-1 transmission. Imaging analysis confirmed that SPC-inhibition impairs cell aggregation in MT-2 cells and blocks p8-induced conduit formation in transfected Jurkat T-cells. Collectively, we identified the SPC as the host cell factor cleaving p12 to p8. Inhibition of p12 cleavage led to the absence of p8, which led to impaired cell-to-cell transmission, and coincided with the absence of p8-induced cell aggregation and conduit formation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013570","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:29:55Z","timestamp":1760117395000},"page":"e1013570","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["HTLV-1 p12 is cleaved to p8 by the signal peptidase complex and its inhibition impairs p8-dependent transmission"],"prefix":"10.1371","volume":"21","author":[{"given":"Florian","family":"Simon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Donhauser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura 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