|Department Affiliations||Department of Oncology|
|SOM Address||Room 351 Cancer Research Building I,|
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3-5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T cell proliferation and cell survival. The Tax oncoprotein promotes T cell transformation, in part via constitutive activation of the NF-kB transcription factor. NF-kB is persistently activated in ATLL and is important for cell survival, although the mechanisms are poorly understood. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-kB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. A long-term goal of the lab is to understand how Tax persistently activates NF-kB signaling and to identify novel treatment strategies for selective blockade of NF-kB in ATLL.
The innate immune response is critical for the initial detection of virus infection and the subsequent activation of adaptive antiviral immunity. RIG-I and MDA5 are RNA helicases that sense viral RNAs and trigger downstream signaling pathways dependent on the adaptor molecule MAVS, which nucleates signaling complexes containing the kinase TBK1 and the transcription factor IRF3. IRF3 activates the expression of type I interferons (IFNa/b), which function in an autocrine or paracrine manner to induce expression of interferon stimulated genes (ISGs) via the JAK/STAT pathway. The activation of antiviral signaling pathways must be tightly controlled to balance the restriction of invading viruses versus collateral damage caused by excessive inflammation. In this area of research, we are interested in identifying and characterizing novel negative regulatory control mechanisms of antiviral signaling pathways.
- Zhou Q, A. Lavorgna, M. Bowman, J. Hiscott and E.W. Harhaj. 2015. Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon.. J Biol Chem. 290(23):14729-39 PMID:25911105
- Jain P, A. Lavorgna, M. Sehgal, L. Gao, R. Ginwala, D. Sagar, E.W. Harhaj, and Z.K. Khan. 2015. Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB. Retrovirology. 12:23. PMID: 25809782
- Shembade, N and E.W. Harhaj. Elucidating dynamic protein-protein interactions and ubiquitination in NF-κB signaling pathways. 2015. Methods Mol Biol. 1280:283-95. PMID: 25736755
- Hyun J, J.C. Ramos, N. Toomey, S. Balachandran, A. Lavorgna, E. Harhaj, and G.N. Barber. Oncogenic human T-cell lymphotropic virus type 1 tax suppression of primary innate immune signaling pathways. 2015. J Virol. 89(9):4880-93 PMID: 25694597
- Choi, YB and E.W. Harhaj. Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses. 2014. Front Biol (Beijing). 9(6):423-436 PMID: 25580106
- Lavorgna, A and E.W. Harhaj. Regulation of HTLV-1 tax stability, cellular trafficking and NF-κB activation by the ubiquitin-proteasome pathway. 2014. Viruses. 6(10):3925-43 PMID: 25341660
- Choi, YB and E.W. Harhaj. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. 2014. PLoS Pathog. 10(10):e1004458 PMID: 25340740
- Lavorgna A, M. Matsuoka and E.W. Harhaj. A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-κB activation and T-cell transformation. 2014. PLoS Pathog. 10(10):e1004418 PMID: 25340344
- Shembade, N, N.S. Harhaj, D.J. Liebl and E.W. Harhaj. 2007. Essential role for TAX1BP1 in the termination of TNF-lpha, IL-1 and LPS-mediated NF-κB and JNK signaling.PMID 17703191 EMBO J. 26: 3910-22. [Highlighted in Nat. Immunol. 2007 8: 1039].
- Shembade, N, N.S. Harhaj, K. Parvatiyar, N.G. Copeland, N.A. Jenkins, L.M. Matesic and E.W. Harhaj. 2008. The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin editing enzyme A20. Nat. Immunol. 9: 254-262. PMID 18246070 [Related News and Views published in Nat. Immunol 9: 227-9; News and Commentary published in Immunol. Cell Biol. 86: 299-300; Faculty of 1000 citation: “Recommended”].
- Shembade, N, K. Parvatiyar, N.S. Harhaj and E.W. Harhaj. 2009. The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-κB signaling. EMBO J. 28: 513-22.PMID 19131965 [Related “Have you seen…?” article published in EMBO J. 28: 455-6].
- Shembade, N, A. Ma and E.W. Harhaj. 2010. Inhibition of NF-κB signaling by A20 through disruption of ubiquitin enzyme complexes. Science. 327: 1135-9 PMID 20185725 [Highlighted in Nat. Immunol. 2010 11: 287; Faculty of 1000 citation: “Must Read”].
- Shembade, N., R. Pujari, N.S. Harhaj, D.W. Abbott and E.W. Harhaj. 2011. The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1.PMID 21765415 Nat. Immunol. 12: 834-843 [Related News and Views published in Nat. Immunol. 2011 12: 815-16].