In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12^I protein

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99-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 noncanonical 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 immunologic synapse following T-cell receptor (TCR) ligation, and downregulates TCR proximal signaling. The uncleaved 12-kDa form of p12^I resides in the ER and interacts with the β and γ_c 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 affect 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.