In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein

Risaku Fukumoto, Vibeke Andresen, Izabela Bialuk, Valentina Cecchinato, Jean Claude Walser, Valerio W. Valeri, Julie M. Nauroth, Antoine Gessain, Christophe Nicot, Genoveffa Franchini

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Abstract

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99-amino acid hydrophobic membrane protein, p12I, 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 p12I 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 p12I 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 affect proteolytic cleavage, suggesting that ER-associated functions of p12I may contribute to the survival and proliferation of the infected T cells in the host.

Original languageEnglish (US)
Pages (from-to)3726-3734
Number of pages9
JournalBlood
Volume113
Issue number16
DOIs
StatePublished - Nov 17 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Fukumoto, R., Andresen, V., Bialuk, I., Cecchinato, V., Walser, J. C., Valeri, V. W., Nauroth, J. M., Gessain, A., Nicot, C., & Franchini, G. (2009). In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein. Blood, 113(16), 3726-3734. https://doi.org/10.1182/blood-2008-04-146928