Fig. 2

p12/p8 protein trafficking and function. (1) In the endoplasmic reticulum (ER), p12 binds to and retains the immature forms of interleukin-2 receptor (IL-2R) β and γ subunits, decreasing their trafficking to the plasma membrane. However, accumulation of the p12/IL-2R γ and β chains in the ER results in signal transducer and activator of transcription 5 (STAT5) phosphorylation in the absence of IL-2, allowing STAT5 translocation to the nucleus to promote cellular proliferation. (2) In the ER, p12 interacts with the immature heavy chains of MHC-I (MHC-I-Hc), binding to its α chain and preventing their interaction with β2 microglobulin (β2m). This leads to its degradation by the proteasome and decreased MHC-I expression at the cell surface. (3) HTLV-1A p12 also mediates the release of calcium ions (Ca²⁺) from the ER by binding calreticulin and calnexin. The release of Ca²⁺ inhibits the binding of calcineurin to the nuclear factor of T-cells (NFAT), preventing its dephosphorylation, nuclear translocation, induction of IL-2 expression and T-cell activation. In addition, p12 can inhibit the NFAT pathway by binding to calcineurin. (4) The p12 protein is proteolytically cleaved in the ER, leading to the formation of p8 that traffics to the cell surface. There, p8 increases T-cell adhesion through lymphocyte function-associated antigen-1 (LFA-1) clustering and promotes the formation of cell-to-cell contacts. (5) Further, p8 enhances the number and length of cellular conduits between T-cells, thereby enhancing signal transduction and HTLV-1 transmission