title: In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein.
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.
authors.affiliation: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Risaku
authors.initials: R
authors.lastname: Fukumoto
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andresen
authors.forename: Izabela
authors.initials: I
authors.lastname: Bialuk
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecchinato
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Walser
authors.forename: Valerio W
authors.initials: VW
authors.lastname: Valeri
authors.forename: Julie M
authors.initials: JM
authors.lastname: Nauroth
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
mesh_terms: 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*
chemical_list: 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
references.citation: Int J Cancer. 1995 Mar 3;60(5):701-6
references.pmid: 7860146
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3625-30
references.pmid: 12824381
references.citation: Virus Res. 1993 Dec;30(3):317-34
references.pmid: 8109163
references.citation: AIDS Res Hum Retroviruses. 2002 Sep 1;18(13):899-902
references.pmid: 12230932
references.citation: J Virol. 1999 Aug;73(8):6460-7
references.pmid: 10400740
references.citation: J Immunol. 2006 May 1;176(9):5463-70
references.pmid: 16622014
references.citation: Virology. 1994 Nov 1;204(2):656-64
references.pmid: 7941334
references.citation: J Exp Med. 2000 Feb 7;191(3):567-72
references.pmid: 10662802
references.citation: AIDS Res Hum Retroviruses. 2005 Jun;21(6):580-2
references.pmid: 15989464
references.citation: Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618-22
references.pmid: 6304725
references.citation: J Virol. 2002 Oct;76(20):10374-82
references.pmid: 12239314
references.citation: J Virol. 2007 Sep;81(17):9088-99
references.pmid: 17582004
references.citation: Virology. 2000 Aug 15;274(1):86-93
references.pmid: 10936091
references.citation: Blood. 2001 Aug 1;98(3):823-9
references.pmid: 11468184
references.citation: J Virol. 1998 May;72(5):4408-12
references.pmid: 9557732
references.citation: Blood. 1995 Nov 15;86(10):3619-39
references.pmid: 7579327
references.citation: J Virol. 1993 Dec;67(12):7701-4
references.pmid: 8230493
references.citation: J Virol. 2001 Aug;75(16):7672-82
references.pmid: 11462039
references.citation: Trends Genet. 2000 Jun;16(6):276-7
references.pmid: 10827456
references.citation: Int J Cancer. 1995 Nov 15;63(4):494-9
references.pmid: 7591256
references.citation: J Virol. 2001 Jul;75(13):6086-94
references.pmid: 11390610
references.citation: AIDS Res Hum Retroviruses. 2004 Oct;20(10):1092-9
references.pmid: 15585100
references.citation: AIDS Res Hum Retroviruses. 2006 May;22(5):466-9
references.pmid: 16706625
references.citation: Oncogene. 2005 Sep 5;24(39):6026-34
references.pmid: 16155609
references.citation: J Virol. 1992 Mar;66(3):1737-45
references.pmid: 1310774
references.citation: J Virol. 2003 Oct;77(20):11027-39
references.pmid: 14512551
references.citation: Oncogene. 2002 Jan 10;21(2):248-59
references.pmid: 11803468
references.citation: J Virol. 2007 Sep;81(18):9707-17
references.pmid: 17609265
references.citation: Blood. 2006 Dec 15;108(13):3979-82
references.pmid: 16917009
references.citation: AIDS Res Hum Retroviruses. 1992 Nov;8(11):1845-9
references.pmid: 1489573
references.citation: J Virol. 1996 Jun;70(6):3599-605
references.pmid: 8648694
references.citation: J Virol. 1993 Apr;67(4):2360-6
references.pmid: 8445734