The RNA genome of the human T-cell leukemia virus type 1 (HTLV-1) codes for proteins involved in infectivity, replication, and transformation. We report in this study the characterization of a novel viral protein encoded by the complementary strand of the HTLV-1 RNA genome. This protein, designated HBZ (for HTLV-1 bZIP factor), contains a N-terminal transcriptional activation domain and a leucine zipper motif in its C terminus. We show here that HBZ is able to interact with the bZIP transcription factor CREB-2 (also called ATF-4), known to activate the HTLV-1 transcription by recruiting the viral trans-activator Tax on the Taxresponsive elements (TxREs). However, we demonstrate that the HBZ/CREB-2 heterodimers are no more able to bind to the TxRE and cyclic AMP response element sites. Taking these findings together, the functional inactivation of CREB-2 by HBZ is suggested to contribute to regulation of the HTLV-1 transcription. Moreover, the characterization of a minus-strand gene protein encoded by HTLV-1 has never been reported until now.Human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis, is a T-cell-tropic virus that belongs to the HTLV-bovine leukemia virus (HTLV-BLV) group of the retrovirus family. Other group members include HTLV-2, BLV, and the simian T-cell leukemia viruses. All retroviruses share similarity in their genome organization, with four genes encoding proteins necessary for the production of infectious virions, the order of these genes being invariably gag, pro, pol, env (from 5Ј to 3Ј) (Fig. 1A). gag codes for internal structural proteins of the virion, pro codes for the viral protease, pol codes for reverse transcriptase, and env codes for envelope glycoproteins of the virion. The expression of the HTLV-1 genome is controlled by two regulatory genes, the rex and tax genes, located in the 3Ј region of the viral genome. Tax is a potent transactivator of viral transcription (5, 30), and Rex acts at the posttranscriptional level by modulating the transport of the viral RNAs (14). Moreover, the HTLV-1 genome carries between the env gene and the 3Ј long terminal repeat (LTR) other open reading frames encoding proteins with unknown functions. All these viral proteins are encoded by the viral plus-strand RNA.The trans-activation of the viral transcription by Tax operates through three 21-bp repeats (6, 28) located in the U3 region of the LTR. These conserved repeats, called Tax-responsive elements (TxREs), contain an imperfect cyclic AMP response element (CRE) (17) that is recognized by CREB (4, 37, 38) and CREM (29), two members of the activating transcription factor/CRE-binding protein (ATF/CREB) family. These factors are characterized by basic leucine zipper (bZIP) C-terminal structures required for DNA binding and protein dimerization. To activate transcription of the HTLV-1 genome, Tax interacts with CREB or CREM bound to the TxREs (4, 38) and then can recruit the transcriptional coactivator CR...

The HIV auxiliary protein Vpr potently blocks the cell cycle at the G2/M transition. Here, we show that G2/M arrest results from untimely activation of the structure-specific endonuclease (SSE) regulator SLX4 complex (SLX4com) by Vpr, a process that requires VPRBP-DDB1-CUL4 E3-ligase complex. Direct interaction of Vpr with SLX4 induced the recruitment of VPRBP and kinase-active PLK1, enhancing the cleavage of DNA by SLX4-associated MUS81-EME1 endonucleases. G2/M arrest-deficient Vpr alleles failed to interact with SLX4 or to induce recruitment of MUS81 and PLK1. Furthermore, knockdown of SLX4, MUS81, or EME1 inhibited Vpr-induced G2/M arrest. In addition, we show that the SLX4com is involved in suppressing spontaneous and HIV-1-mediated induction of type 1 interferon and establishment of antiviral responses. Thus, our work not only reveals the identity of the cellular factors required for Vpr-mediated G2/M arrest but also identifies the SLX4com as a regulator of innate immunity.

The human T-cell leukemia virus type I (HTLV-I

Human T-cell leukemia virus type I (HTLV-I) bZIP factor (HBZ) is a viral basic leucine zipper protein that was originally described as a partner of cAMP response element binding protein-2 and as a repressor of HTLV-I viral transcription. In addition, HBZ is able to interact with the activator protein-1 (AP-1) transcription factors c-Jun and JunB, the interaction with c-Jun leading to a transcriptional repression of AP-1-regulated genes. Here we show that HBZ also interacts with JunD in vitro and in vivo, and that this association occurs via the bZIP domain of the two proteins. Moreover, we show that HBZ can activate JunD-dependent transcription and that its amino-terminus is required.