Abstract
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 down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12(I) resides in the ER and interacts with the beta and gamma(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.
Publication types
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
COS Cells
-
Calnexin / genetics
-
Calnexin / metabolism
-
Calreticulin / genetics
-
Calreticulin / metabolism
-
Cell Proliferation
-
Cell Survival / genetics
-
Chlorocebus aethiops
-
Golgi Apparatus / genetics
-
Golgi Apparatus / metabolism
-
HTLV-I Infections / genetics
-
HTLV-I Infections / metabolism*
-
HeLa Cells
-
Histocompatibility Antigens Class I / genetics
-
Histocompatibility Antigens Class I / metabolism
-
Human T-lymphotropic virus 1 / genetics
-
Human T-lymphotropic virus 1 / metabolism*
-
Humans
-
Hydrophobic and Hydrophilic Interactions
-
Immunologic Capping / genetics
-
Immunological Synapses / genetics
-
Immunological Synapses / metabolism
-
Interleukin Receptor Common gamma Subunit / genetics
-
Interleukin Receptor Common gamma Subunit / metabolism
-
Interleukin-2 Receptor beta Subunit / genetics
-
Interleukin-2 Receptor beta Subunit / metabolism
-
Jurkat Cells
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mutation*
-
Protein Binding / genetics
-
Protein Sorting Signals / genetics
-
Protein Transport / genetics
-
Receptors, Antigen, T-Cell
-
Viral Regulatory and Accessory Proteins / genetics
-
Viral Regulatory and Accessory Proteins / metabolism*
Substances
-
Calreticulin
-
Histocompatibility Antigens Class I
-
IL2RB protein, human
-
IL2RG protein, human
-
Interleukin Receptor Common gamma Subunit
-
Interleukin-2 Receptor beta Subunit
-
Membrane Proteins
-
Protein Sorting Signals
-
Receptors, Antigen, T-Cell
-
Viral Regulatory and Accessory Proteins
-
p12I protein, Human T-lymphotropic virus 1
-
Calnexin