Negative regulation of NF-κB and inflammation

My laboratory focuses on understanding how danger-sensing receptors of the innate and adaptive immune systems activate transcription factor, NF-κB. NF-κB plays a critical role in regulating the expression of a large number of genes involved in immune, inflammatory and cell death processes. Activation of NF-κB transcription factors by receptors is essential for host defense. However, after danger is eliminated, NF-κB signaling needs to be tightly downregulated for the maintenance of tissue homeostasis. Dysregulation of NF-κB leading to its persistent activation has been linked to malignancy, chronic inflammation and autoimmune diseases. A20 ubiquitin-editing complex tightly regulates NF-κB activation. However, the mechanism of A20 ubiquitin-editing complex activation is not known. We wish to understand the mechanism that activates A20 ubiquitin-editing complex that leads to termination of NF-κB and maintenance of tissue homeostasis.

Mechanism of HTLV-1 Tax mediated NF-κB activation

Human T-cell leukemia virus type 1 (HTLV-1) is retrovirus that has been linked to a variety of clinical diseases, including an aggressive and fatal cancer called adult T cell leukemia (ATL), neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) that is clinically very similar to multiple sclerosis. HTLV-I predominantly infects CD4+ T cells. NF-κB is one of the main targets of the HTLV-1 encoded oncoprotein Tax to transform cells. Moreover, NF-κB is essential for the survival of HTLV-1 transformed cell lines and ATL leukemic cells. HTLV-1 Tax targets A20 ubiquitin-editing complex to persistently activate NF-κB. However, the fundamental mechanisms of Tax mediated inactivation of A20 ubiquitin-editing complex are poorly understood. Our lab is mainly interested in determining the mechanism of Tax mediated NF-κB activation.

Negative regulation of JAK/STAT signaling pathway by HTLV-1 Tax

Viral infected cells produce type I interferons (IFN-α and IFN-β). IFN-I displays both autocrine and paracrine effects. Engagement of the IFN-I receptors (IFNAR-1 and IFNAR-2) at the cell surface induces activation of Jak1/Tyk2 and STAT1/STAT2 signaling cascade that subsequently promotes the expression of a large number of anti-viral effectors known as interferon-stimulated genes (ISGs), for example PKR. PKR limits viral proteins synthesis, thus hindering viral replication. HTLV-1-infection prevents IFN-I signaling by decreasing Tyk2 and STAT2 phosphorylation. However, the molecular mechanisms of inactivation of Jak1/STAT pathway by HTLV-1 are not known and remain the primary focus of our laboratory.

Our lab is currently using variety of biochemical and genetic strategies to identify cellular factors involved in HTLV-1 Tax mediated regulation of NF-κB and Jak/STAT signaling pathways.

Shembade N, Pujari R, Harhaj NS, Derek AW, Harhaj EW.The kinase IKKa inhibits activation of the transcription factor NF-kB by phosphorylating the regulatory molecule TAX1BP1. Nature Immunology 12, 834–843 (2011)

Shembade N, Pujari R,  Harhaj NS, Derek AW, Harhaj EW.(2011)IKKα takes control of canonical NF-κB activation reply. Nature Immunology 12, 815–816 (2011)

Charoenthongtrakul S, Zhou Q, Shembade N, Harhaj NS, and Harhaj EW. (2011) HTLV-I Tax inhibits innate antiviral signaling via NF-B-dependent induction. J Virol.85(14):6955-62

Shembade N, Ma A, Harhaj EW. (2010) Inhibition of NF-kB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 26;327(5969):1135-9.

Shembade N, Ma A, Harhaj EW. (2010) Cell biology. Turning off inflammation signaling reply. Science.  26;327(5969):1093-4

Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW. (2009) The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kB signalling. EMBO J.2009 Mar 4;28(5):513-22.

Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW. (2009) RNF11, A new piece in the A20 puzzle reply EMBO J. Mar 4;28(5):455-6.

Shembade N,Harhaj NS, Parvatiyar K, Copeland NG, Jenkins NA, Matesic LE, Harhaj EW. (2008) The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nature Immunology. Mar;9(3):254-62.

Shembade N,Harhaj NS, Parvatiyar K, Copeland NG, Jenkins NA, Matesic LE, Harhaj EW. (2008) Itching to end NF-kappaB reply. Nature Immunology.Mar;9(3):227-9

Sass G, Shembade ND, Haimerl F, Lamoureux N, ashemolhosseini S, Tannapfel A, Tiegs G. (2007) TNF pretreatment interferes with mitochondrial apoptosis in the mouse liver by A20-mediated down-regulation of Bax. J. Immunol.Nov 15;179(10):7042-9.

Shembade N, Harhaj NS, Yamamoto M, Akira S, Harhaj EW. (2007) The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation J Virol.Dec;81(24):13735-42.

Shembade N, Harhaj NS, Liebl DJ, Harhaj EW. (2007) Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. EMBO J.Sep 5;26(17):3910-22.

Shembade N, Harhaj NS, Liebl DJ, Harhaj EW. (2007) The terminator “Research Highlights” Nature Immunology. 8, 1039.

Sass G, Shembade ND Tiegs G. (2005) Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling. Biochem J.Jan 15;385(Pt 2):537-44.