Protein Profile of Tax-associated Complexes

Abstract

Infection with human T-cell leukemia virus type 1 (HTLV-1) results in adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax, a 40-kDa protein, regulates viral and cellular transcription, host signal transduction, the cell cycle, and apoptosis. Tax has been shown to modulate cellular CREB and NFB pathways; however, to date, its role in binding to various host cellular proteins involved in tumorigenesis has not been fully described. In this study, we describe the Tax-associated proteins and their functions in cells using several approaches. Tax eluted from a sizing column mostly at an apparent molecular mass of 1800 kDa. Following Tax immunoprecipitation, washes with high salt buffer, two-dimensional gel separation, and mass spectrometric analysis, a total of 32 proteins was identified. Many of these proteins belong to the signal transduction and cytoskeleton pathways and transcription/chromatin remodeling. A few of these proteins, including TXBP151, have been shown previously to bind to Tax. The interaction of Tax with small GTPase-cytoskeleton proteins, such as ras GAP 1m , Rac1, Cdc42, RhoA, and gelsolin, indicates how Tax may regulate migration, invasion, and adhesion in T-cell cancers. Finally, the physical and functional association of Tax with the chromatin remodeling SWI/SNF complex was assessed using in vitro chromatin remodeling assays, chromatin remodeling factor BRG1 mutant cells, and RNA interference experiments. Collectively, Tax is able to bind and regulate many cellular proteins that regulate transcription and cytoskeletal related pathways, which might explain the pleiotropic effects of Tax leading to T-cell transformation and leukemia in HTLV-1-infected patients.Infection with human T-cell leukemia virus type 1 (HTLV-1) 1 results in adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The Tax protein encoded by HTLV-1 plays a central role in the development of both adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Although Tax itself does not bind to DNA directly or function as an enzyme, its ability to regulate multiple cellular responses is conferred by its protein-protein interactions with various host cellular factors. Importantly, HTLV-1-mediated activation of the host T-cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction, cell cycle control, and apoptosis. Therefore, understanding how Tax controls these pathways is of significant importance. Tax targets several transcriptional pathways including CREB/activating transcription factor, NFB, and multiple other factors including cell cycle regulators, such as cyclins D2 and D3, the mitotic checkpoint regulator MAD1, the cyclin-dependent kinases (Cdk) Cdk4 and Cdk6, Cdk inhibitors (p16/INK4A and p21/Waf1), and the tumor suppressor p53 (1). Moreover, Tax regulation is observed at both nuclear (e.g. CREB-dependent) and cytoplasmic (e.g. NFB-dependent) levels, functioning through shuttl...

Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1

“…1C, lane 4) but not to GST (lane 2). Notably, our data on the interaction of TAX1BP1 and Tax are consistent with findings from yeast two-hybrid and mass spectrometric analyses of Tax-associated proteins in HTLV-1-transformed MT2 and C8166 lymphoblastic cells (37,38).…”

“…Newly identified Tax-binding proteins, such as tropomyosin 5 and TORC1/2/3, also have a coiled-coil domain (17,18,38). In the case of TORC1/2/3, the Tax-binding domain is also within the coiled-coil region (17).…”

Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression

“…[16][17][18][19][20] The Ras-ERK pathway is also the target of the HTLV-1 oncogenic protein Tax. 33,34 Recently, Ras-ERK signaling was shown to be particularly important for Taxmediated protection of cells from apoptosis. 35 Our study demonstrates that Roc can block the Ras-ERK signaling pathway and thereby downregulate c-FLIP expression through inhibition of eIF4E function, a key factor that controls the rate-limiting step of translation.…”

Human T-lymphotropic Virus, Type 1, Tax Protein Triggers Microtubule Reorientation in the Virological Synapse

“…Recent proteomic studies suggest that Tax protein interacts with cytoskeleton proteins families, such as gelsolin and actin, and with certain proteins that influence cytoskeleton dynamics, such as annexin, myosin light chain kinases, and myotubularin-related protein. Tax protein also interacts with several small GTPases including Cdc42, RhoA, and Rac1 (49). These proteins are known for their regulatory role in actin dynamics leading to cellular transformation (50 -52).…”