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Edward W. Harhaj, M.S., Ph.D.

Photo of Dr. Edward W. Harhaj, M.S., Ph.D.

Associate Professor of Oncology

Research Interests: Mechanisms of NF-kB activation and oncogenesis by the HTLV-1 Tax oncoprotein; Regulation of antiviral innate immune signaling more



  • Associate Professor of Oncology

Departments / Divisions



  • B.A., Bucknell University (Pennsylvania) (1992)
  • M.S., Bucknell University (Pennsylvania) (1994)
  • Ph.D., Pennsylvania State University - College of Medicine - Hershey (Pennsylvania) (1999)

Research & Publications

Research Summary

Mechanisms of HTLV-1 Tax-mediated NF-κB activation
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that has been linked to the development of two distinct diseases in humans: 1) a neuroinflammatory disorder termed HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) that is clinically similar to multiple sclerosis (MS), and 2) an aggressive CD4+CD25+ malignancy known as adult T-cell leukemia/lymphoma (ATLL). The NF-κB transcription factor is one of the primary targets of the HTLV-1 encoded oncoprotein Tax to transform cells. Furthermore, NF-κB is required for the survival of HTLV-1 transformed cell lines and ATL leukemic cells. Therefore, we are interested in determining the mechanisms of Tax-mediated NF-κB activation. We have found that Tax is polyubiquitinated in a noncanonical manner whereby the ubiquitin chains are linked via lysine 63 (K63) rather than lysine 48 (K48) that triggers proteosomal degradation. K63-linked polyubiquitination of Tax likely confers a scaffolding function that enables the recruitment of signaling molecules that activate the IαB kinase (IKK) and NF-κB. We have identified the E2 ubiquitin conjugating enzyme Ubc13 as essential for both Tax ubiquitination and NF-κB activation. Future studies will use proteomics, yeast two-hybrid and shRNA screens to identify host factors that regulate Tax ubiquitination and Tax-induced NF-κB activation.

Negative regulation of NF-κB and inflammation
The NF-κB transcription factor is critical for the induction of genes regulating innate and adaptive immunity. NF-κB is tightly regulated to ensure that activation is only transient upon stimulation by cytokines such as tumor necrosis factor alpha (TNF-α and interleukin-1 (IL-1). Dysregulation of NF-κB leading to its persistent activation has been linked to chronic inflammation and autoimmunity. It has also become increasingly clear that chronic inflammation may fuel cancer growth and progression. The zinc finger protein A20 (also known as TNFAIP3) has been shown to be essential for the termination of NF-κB signaling in tumor necrosis factor receptor (TNFR) and Toll-like receptor 4 (TLR4)/IL-1R signaling pathways by targeting key signaling molecules such as RIP1 and TRAF6 for inactivation. Mice lacking A20 die prematurely of multi-organ inflammation and cachexia. In addition, specific polymorphisms within the A20 genomic region have been associated with a number of human autoimmune diseases such as rheumatoid arthritis, systemic lupus erythomatosus and Crohn’s disease. Additional studies have demonstrated loss-of-function mutations or deletions within A20 that are associated with B-cell lymphomas. Despite the importance of A20 in limiting inflammatory responses and tumor growth, little is known about how A20 is regulated and also if other molecules are essential for the termination of NF-κB signaling. Our laboratory has identified several key regulatory proteins that are required for the function of A20 and the down-regulation of NF-κB signaling. A20, TAX1BP1, Itch and RNF11 together constitute the A20 ubiquitin-editing complex that plays a critical role in the repression of NF-κB signaling and inflammation. In response to stimulation with proinflammatory cytokines, A20 inducibly interacts with TAX1BP1, Itch and RNF11 upon phosphorylation of TAX1BP1 by the IKK subunit, IKKα. In addition, HTLV-1 Tax promotes persistent NF-κB signaling and oncogenesis, in part by blocking TAX1BP1 phosphorylation and inactivating the function of A20. In future studies, we will determine the precise roles of each of the subunits of the A20 ubiquitin-editing complex by performing biochemical studies and gene targeting in mice.

Selected Publications

View all on Pubmed

Choi YB and Harhaj EW. HTLV-1 Tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathogens. 2014;10(10)e1004458.

Shembade N, Pujari R, Harhaj NS, Abbott DW and Harhaj EW. The kinase IKKa inhibits activation of the transcription factor NF-kB by phosphorylating the regulatory molecule TAX1BP1. Nature Immunol. 2011;12: 834-843.

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

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

Xiao G*, Harhaj EW* and Sun SC. NF-kB-inducing kinase regulates the processing of NF-kB2 p100. Molecular Cell. 2001;7(2):401-9. *Equal contribution

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