HTLV-1 p12(I) protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells.
The p12(I) protein, encoded by the pX open reading frame I of the human T-lymphotropic virus type 1 (HTLV-1), is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p12(I) contains 4 minimal proline-rich, src homology 3-binding motifs (PXXP), a characteristic commonly found in proteins involved in signaling pathways, it has not been known whether p12(I) has a role in modulating intracellular signaling pathways. This study demonstrated that p12(I) binds to the cytoplasmic domain of the interleukin-2 receptor (IL-2R) beta chain that is involved in the recruitment of the Jak1 and Jak3 kinases. As a result of this interaction, p12(I) increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R beta and gamma(c) chains and Jak3. Transduction of primary human peripheral blood mononuclear cells (PBMCs) with a human immunodeficiency virus type 1-based retroviral vector expressing p12(I) also resulted in increased STAT5 phosphorylation and DNA binding. However, p12(I) could increase proliferation of human PBMCs only after stimulation of T-cell receptors by treatment of cells with low concentrations of alphaCD3 and alphaCD28 antibodies. In addition, the proliferative advantage of p12(I)-transduced PBMCs was evident mainly at low concentrations of IL-2. Together, these data indicate that p12(I) may confer a proliferative advantage on HTLV-1-infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of infected T cells in vivo. (Blood. 2001;98:823-829)
Nicot
C
C
National Cancer Institute, Basic Research Laboratory, Bethesda, MD 20892, USA.
Mulloy
J C
JC
Ferrari
M G
MG
Johnson
J M
JM
Fu
K
K
Fukumoto
R
R
Trovato
R
R
Fullen
J
J
Leonard
W J
WJ
Franchini
G
G
D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D015490:HTLV-I Infections / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008894:Milk Proteins; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D009856:Oncogene Proteins, Viral; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1