In Vivo Genetic Mutations Define Predominant Functions of the Human T-Cell Leukemia/Lymphoma Virus p12I Protein.

The human T-cell leukemia/lymphoma virus Type 1 (HTLV-1) ORF-I encodes, a ninety-nine amino acid hydrophobic membrane protein, p12^I that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12^I. The removal of a non-canonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12^I is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8 kDa protein. The 8 kDa protein in turn traffics to the cell surface, is recruited to the immunological synapse following T-cell receptor (TCR) ligation and down-regulates TCR proximal signaling. The uncleaved 12 kDa form of p12^I resides in the ER and interacts with the β and γc chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals predominant amino acid substitutions within ORF-I that inhibits proteolytic cleavage, suggesting that ER associated functions of p12^I may contribute to the survival and proliferation of the infected T-cells in the host.