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

Risaku Fukumoto (1) , Vibeke Andresen (1) , Izabela Bialuk (1) , Valentina Cecchinato (1) , Jean-Claude Walser (2) , Valerio W. Valeri (1) , Julie M. Nauroth (1) , Antoine Gessain (3) , Christophe Nicot (4) , Genoveffa Franchini (1)

1 Animal Models and Retroviral Vaccines Section
2 Section on Genomic Structure and Function
3 Epidémiologie et Physiopathologie des Virus Oncogènes
4 Department of Microbiology, Molecular genetics and Immunology

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.

Domaines: Microbiologie et Parasitologie

Risaku Fukumoto, Vibeke Andresen, Izabela Bialuk, Valentina Cecchinato, Jean-Claude Walser, et al.. In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein.. Blood, 2009, 113 (16), pp.3726-34. ⟨10.1182/blood-2008-04-146928⟩. ⟨pasteur-00531275⟩