Tax Blog

Recent HTLV-1 articles at Retrovirology

K Jeang — Mon, 20 Feb 2012 18:22:45 GMT

Here are four recent HTLV-1 articles published in Retrovirology (www.retrovirology.com ). All the articles are Open Access which means that you can read them all at Retrovirology in full text in a subscription-free manner.

1. Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease.
Enose-Akahata Y, Matsuura E, Tanaka Y, Oh U, Jacobson S.
Retrovirology. 2012 Feb 15;9(1):16. [Epub ahead of print]
PMID:
22335964

2. How the DNA damage response determines the fate of HTLV-1 Tax-expressing cells.
Boxus M, Willems L.
Retrovirology. 2012 Jan 5;9(1):2. [Epub ahead of print]
PMID:
22221708

3. Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers.
Takamori A, Hasegawa A, Utsunomiya A, Maeda Y, Yamano Y, Masuda M, Shimizu Y, Tamai Y, Sasada A, Zeng N, Choi I, Uike N, Okamura J, Watanabe T, Masuda T, Kannagi M.
Retrovirology. 2011 Dec 7;8:100.
PMID:
22151736

4. ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells.
Hagiya K, Yasunaga J, Satou Y, Ohshima K, Matsuoka M.
Retrovirology. 2011 Mar 17;8:19.
PMID:
21414204

Tax binding protein Tax1BP1 & NFkB activation

K Jeang — Sat, 15 Mar 2008 21:23:00 GMT

Two recent papers (see below) comment on the importance of Tax binding protein Tax1BP1 and the A20 deubiquitinase for activated NFkB signaling through TRAF6. An emerging model suggests that K63 ubiquitination of TRAF6 activates NFkB signaling, and that Tax1BP1 recruits A20 to deubiquinate TRAF6 to silence NFkB signaling. In this context, Tax can be envisioned to prevent Tax1BP1's recruitment of A20; thereby Tax prevents de-Ub of TRAF6 by A20. Preventing TRAF6 de-ubiquitination is, then, another mechanism through which Tax activates NFkB.

The two relevant papers to consult are:

The EMBO Journal (2007) 26, 3910–3922, doi:10.1038/sj.emboj.7601823
Published online 16 August 2007

Essential role for TAX1BP1 in the termination of TNF--, IL-1- and LPS-mediated NF-B and JNK signaling

Noula Shembade¹, Nicole S Harhaj¹, Daniel J Liebl² and Edward W Harhaj¹

¹ Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL, USA
² The Miami Project to Cure Paralysis and Department of Neurosurgery, Miller School of Medicine, The University of Miami, Miami, FL, USA

To whom correspondence should be addressed
Edward W Harhaj, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, 1550 NW 10 Avenue, Miami, FL 33136, USA. Tel.: +1 305 243 7893; Fax: +1 305 243 6410; E-mail: eharhaj@med.miami.edu

Received 27 February 2007; Accepted 19 July 2007; Published online 16 August 2007.

The EMBO Journal (2008) 27, 629–641, doi:10.1038/emboj.2008.5
Published online 31 January 2008

Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-B activation

Hidekatsu Iha^{1, 6}^{, 7}, Jean-Marie Peloponese¹^{, 7}, Lynn Verstrepen², Grzegorz Zapart³, Fumiyo Ikeda³, C Dahlem Smith⁴, Matthew F Starost⁵, Venkat Yedavalli¹, Karen Heyninck², Ivan Dikic³, Rudi Beyaert² and Kuan-Teh Jeang¹

¹ Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
² Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Ghent University—VIB, Ghent (Zwijnaarde), Belgium
³ Institute for Biochemistry II, Goethe University Medical School, Frankfurt, Germany
⁴ Pathology/Histotechnology Laboratory, SAIC-Frederick Inc., NCI-FCR, Frederick, MD, USA
⁵ Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA
⁶ Department of Infectious Diseases, Faculty of Medicine, Oita University Idaiga-oka, Hasama Yufu, Japan

To whom correspondence should be addressed
Kuan-Teh Jeang, Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 306, 9000 Rockville Pike, Bethesda, MD 20892-0460, USA. Tel.: +1 301 496 6680; Fax: +1 301 480 3686; E-mail: kjeang@niaid.nih.gov

⁷ These authors contributed equally to this work

Received 18 September 2007; Accepted 4 January 2008; Published online 31 January 2008.

Human T Lymphotropic Virus Type 1 protein tax reduces histone levels

K Jeang — Tue, 12 Feb 2008 16:30:00 GMT

Paul Laybourn has a paper in Retrovirolgy (www.retrovirology.com) on Tax reduces histone levels. Full text of the paper can be accessed at http://www.retrovirology.com/content/5/1/9/abstract

Research

Human T Lymphotropic Virus Type 1 protein tax reduces histone levels

James M Bogenberger and Paul J Laybourn

Retrovirology 2008, 5:9doi:10.1186/1742-4690-5-9


Published:	31 January 2008

Abstract (provisional)

Background

Human T-Lymphotropic Virus Type-1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATLL). The virally encoded Tax protein is thought to be necessary and sufficient for T-cell leukemogenesis. Tax promotes inappropriate cellular proliferation, represses multiple DNA repair mechanisms, deregulates cell cycle checkpoints, and induces genomic instability. All of these Tax effects are thought to cooperate in the development of ATLL.

Results

In this study, we demonstrate that histone protein levels are reduced in HTLV-1 infected T-cell lines (HuT102, SLB-1 and C81) relative to uninfected T-cell lines (CEM, Jurkat and Molt4), while the relative amount of DNA per haploid complement is unaffected. In addition, we show that replication-dependent core and linker histone transcript levels are reduced in HTLV-1 infected T-cell lines. Furthermore, we show that Tax expression in Jurkat cells is sufficient for reduction of replication-dependent histone transcript levels.

Conclusions

These results demonstrate that Tax disrupts the proper regulation of replication-dependent histone gene expression. Further, our findings suggest that HTLV-1 infection uncouples replication-dependent histone gene expression and DNA replication, allowing the depletion of histone proteins with cell division. Histone proteins are involved in the regulation of all metabolic processes involving DNA including transcription, replication, repair and recombination. This study provides a previously unidentified mechanism by which Tax may directly induce chromosomal instability and deregulate gene expression through reduced histone levels.

Ubiquitination of HTLV-I Tax

K Jeang — Wed, 09 Jan 2008 22:03:00 GMT

Susan Marriott has a nice paper on Ubiquitination of Tax published in December in Retrovirology.

The abstract for the paper is below. The full text of the paper can be accessed at http://www.retrovirology.com/content/4/1/95

Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export

Michael L. Gatza, Tajhal Dayaram and Susan J. Marriott

Retrovirology 2007, 4:95doi:10.1186/1742-4690-4-95


Published:	14 December 2007

Abstract (provisional)

Background

The HTLV-I oncoprotein, Tax, is a pleiotropic protein whose activity is partially regulated by its ability to interact with, and perturb the functions of, numerous cellular proteins. Tax is predominantly a nuclear protein that localizes to nuclear foci known as Tax Speckled Structures (TSS). We recently reported that the localization of Tax and its interactions with cellular proteins are altered in response to various forms of genotoxic and cellular stress. The level of cytoplasmic Tax increases in response to stress and this relocalization depends upon the interaction of Tax with CRM1. Cellular pathways and signals that regulate the subcellular localization of Tax remain to be determined. However, post-translational modifications including sumoylation and ubiquitination are known to influence the subcellular localization of Tax and its interactions with cellular proteins. The sumoylated form of Tax exists predominantly in the nucleus while ubiquitinated Tax exists predominantly in the cytoplasm. Therefore, we hypothesized that post-translational modifications of Tax that occur in response to DNA damage regulate the localization of Tax and its interactions with cellular proteins.

Results

We found a significant increase in mono-ubiquitination of Tax in response to UV irradiation. Mutation of specific lysine residues (K280 and K284) within Tax inhibited DNA damage-induced ubiquitination. In contrast to wild-type Tax, which undergoes transient nucleocytoplasmic shuttling in response to DNA damage, the K280 and K284 mutants were retained in nuclear foci following UV irradiation and remained co-localized with the cellular TSS protein, sc35.

Conclusions

This study demonstrates that the localization of Tax, and its interactions with cellular proteins, are dynamic following DNA damage and depend on the post-translational modification status of Tax. Specifically, DNA damage induces the ubiquitination of Tax at K280 and K284. Ubiquitination of these residues facilitates the dissociation of Tax from sc35-containing nuclear foci, and stimulates nuclear export of Tax through the CRM1 pathway.