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 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.
Fukumoto
Risaku
R
Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA.
Andresen
Vibeke
V
Bialuk
Izabela
I
Cecchinato
Valentina
V
Walser
Jean-Claude
JC
Valeri
Valerio W
VW
Nauroth
Julie M
JM
Gessain
Antoine
A
Nicot
Christophe
C
Franchini
Genoveffa
G
D000818:Animals; D019556:COS Cells; D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002522:Chlorocebus aethiops; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007152:Immunologic Capping / Q000235:genetics; D054992:Immunological Synapses / Q000235:genetics / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D021382:Protein Sorting Signals / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D011948:Receptors, Antigen, T-Cell; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*
D037282:Calreticulin; D015395:Histocompatibility Antigens Class I; C508020:IL2RB protein, human; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D053646:Interleukin-2 Receptor beta Subunit; D008565:Membrane Proteins; D021382:Protein Sorting Signals; D011948:Receptors, Antigen, T-Cell; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1; D037281:Calnexin
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