Project I: Uncontrolled activation of innate immune receptors by the pathogens can cause chronic inflammation and autoimmune diseases. Shembade’s laboratory focuses on understanding the mechanisms of negative regulation of the transcription factor NF-κB activated by the innate immune receptors. Activation of NF-κB is critical to eliminate pathogens and to maintain tissue homeostasis. NF-κB activation needs to be tightly regulated after the danger is eliminated. The ubiquitin-editing enzyme A20 complex tightly regulates NF-κB activation. The mechanisms of the ubiquitin-editing enzyme A20 complex activation are not known. Thus, they wish to understand the mechanisms that activate the A20 complex and lead to the termination of NF-κB activation and maintenance of tissue homeostasis.
Project II: Chronic activation of NF-κB is essential for the survival of leukemia and lymphoma caused by oncogenic viruses, such as EBV, KSHV, and HTLV-1 infected cells. Viral oncogenes, LMP-1 of EBV, vFLIP, and vGPCR of KSHV and Tax of HTLV-1, are hijacking and post-translationally modifying host factors to maintain chronic NF-κB activation in leukemias and lymphomas. However, the host factors that are post-translationally modified are not fully known. Thus another focus of his laboratory is to identify the mechanisms and host factors that post-translationally modified by the viral oncogenes to maintain chronic NF-κB activation in leukemias and lymphomas.
Project III: Type I interferons (IFN-α and IFN-β) and type II interferon (IFN-γ) are induced in response to infections with viruses or bacteria. IFNs bind to their cognate receptor, which plays important roles in host defense against invading pathogens. Type I interferons provide protection against many viral infections, whereas type II interferon is essential for host defense against some bacterial and parasitic pathogens. Interestingly, numerous studies have also found that functional dysregulation of either interferon response can lead to chronic pathological conditions associated with numerous human diseases, including tissue damage and autoimmunity. Type I and II IFN signaling pathways are dysregulated in oncogenic virus-infected cells to maintain chronic inflammation condition, initiate, and develop tumors. However, the molecular mechanisms and the host factors that are involved in regulating interferon receptors are poorly understood. The overall objective of this proposal is to determine the molecular mechanisms of action of a host protein, P-2 (also known as MPEG-1), on Type I and II IFN signaling pathways and oncogenic virus-infected cells.