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"Distinct Expression Profile of Interferon-lambda4 Defines its Unique Biological Function in HCV Pathogenesis"

by
Satya Singh
Cell Biology, Neuroscience and Physiology Program
B.S. 2002, Banaras Hindu University, India
M.S. 2011, New York University, New York


Thesis Advisor: Sergei V. Kotenko, Ph.D. Professor
Department of Microbiology, Biochemistry & Molecular Genetics
Center for Immunity and Inflammation
Cancer Institute of New Jersey

Tuesday, September 26, 2017
10:00 A.M., Cancer Center G1196


Abstract

Interferons (IFNs) are antiviral proteins produced in response to viral infections. IFNs are classified into three different types, type I, type II and type III (or ) IFNs. In humans, IFN-s are represented by IFN-1, IFN-2, IFN-3 and a recently identified IFN-4, which shares only a limited homology with other IFN-s. There is a frequently occurring frame shift mutation in the Ifnl4 gene that can be used as a predictive marker for the responsiveness of patients chronically infected with HCV to IFN--based therapies. Paradoxically, the presence of the intact Ifnl4 gene is associated with poor response to anti-HCV treatments, suggesting a unique function for IFN-4. Unlike other IFN-s, IFN-4 is not well-secreted from human cells. The reasons for the poor secretion of IFN-4 and whether it is linked to its unique biological activities are unknown. Our results show that IFN-4 has a distinct pattern of secretion. IFN-4 is secreted as a soluble protein and as an extracellular matrix (ECM)-bound protein. We show that Glycosaminoglycans (GAGs) binding sites and unusual N-linked glycosylation site within the IFN-4 protein were identified as sequence motifs governing the unique secretion profile of IFN-4. Moreover, although both forms of IFN-4 are biologically active, the ECM-bound IFN-4 induces long lived signaling leading to prolonged desensitization of cells to endogenous or exogenous type I IFN. Thus, the presence of ECM-bound IFN-4 protein provides a plausible explanation for the detrimental role of active IFN-4 protein in HCV infection.


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