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 Blood, 16 April 2009, Vol. 113, No. 16, pp. 3726-3734.
Prepublished online as a Blood First Edition Paper on September 12, 2008; DOI 10.1182/blood-2008-04-146928.

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IMMUNOBIOLOGY

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

Risaku Fukumoto1,*, Vibeke Andresen1,*, Izabela Bialuk1, Valentina Cecchinato1, Jean-Claude Walser2, Valerio W. Valeri1, Julie M. Nauroth1, Antoine Gessain3, Christophe Nicot4, and Genoveffa Franchini1

1 Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD; 2 Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; 3 Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Batiment Lwoff, Institut Pasteur, Paris, France; and 4 Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City

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 p12I. 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 down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12I resides in the ER and interacts with the β 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 p12I may contribute to the survival and proliferation of the infected T cells in the host.


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