PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo.
HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1deltaPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(deltaPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFkappaB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1- and HTLV-2-induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1deltaPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.
Xie
Li
L
Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Rd, Columbus, OH 43210, USA.
Yamamoto
Brenda
B
Haoudi
Abdelali
A
Semmes
O John
OJ
Green
Patrick L
PL
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000235:genetics*; D004195:Disease Models, Animal; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D011817:Rabbits; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000378:metabolism* / Q000637:transplantation
D016356:Gene Products, tax