Inhibition of the signal peptidase complex blocks cleavage of HTLV-1 ORF-I encoded p12 to p8 and impairs virus transmission

Infection with the oncogenic delta-retrovirus Human T-cell Leukemia Virus Type 1 (HTLV-1) causes aggressive CD4+ T-cell malignancy or progressive neuroinflammatory disorders. The HTLV-1 accessory protein p8 is important for viral persistence and induces formation of cellular conduits, thereby enhancing HTLV-1 cell-to-cell transmission. p8 is a cleavage product of its precursor protein p12. To date, host factors cleaving p12 to p8 remain unknown impeding delineation of functions of p12 from those of p8. Here, we report that p12 carries a signal peptide (SP) that is cleaved by the signal peptidase complex (SPC) to generate p8. SPC-inhibition blocked p12 cleavage, impaired conduit formation and cell-to-cell transmission. Based on these findings, computational predictions allowed us to generate cleavage-deficient p12 mutants. Thus, we identified the host cell factors cleaving p12 to p8 harboring the potential to lower the viral burden and to study the functions of p12 and p8 independently of each other.