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Professor Department of Microbiology and Immunology Ph.D., Northwestern University, 1980 |
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E-mail: |
patrick.hearing@stonybrook.edu |
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Research |
Patrick Hearing research My laboratory studies the human DNA tumor virus adenovirus (Ad). Ad is an outstanding model system to study the regulation of numerous cellular processes including proliferation, gene expression, apoptosis, and host antiviral responses to infection. Recombinant Ad vectors also are promising agents for therapeutic gene delivery and as vaccine vectors. Ad generally causes mild infections of the respiratory and gastrointestinal tracts, but Ad infection may be severe in infants, the elderly and in immunocompromised individuals. Our research focuses on innate antiviral responses that are elicited during the early stage of viral infection and viral mechanisms that counteract these responses. The results provide fundamental insights into cellular and viral processes that inhibit or promote the viral replication program. Adenovirus induction of an interferon (IFN) response. The Ad DNA genome is sensed by cellular receptors which triggers an IFN response. IFNs are cytokines that have pleiotropic effects and play important roles in innate and adaptive immunity. IFNs have broad antiviral properties and function by different mechanisms. Our data demonstrate that both type I IFNalpha and type II IFNgamma block wild-type Ad replication in primary human bronchial epithelial cells and normal human diploid fibroblasts. IFNs inhibit viral gene expression and our studies focus on the mechanistic basis of this process and what IFN signaling pathway(s) is involved. We found that IFNs promote persistent Ad infection. Our results reveal a novel mechanism by which Ads utilize IFN signaling to suppress lytic virus replication and to promote persistent infection. Our studies are focused on understanding this process. Adenovirus induction of DNA damage response (DDR). Viruses with linear, double-stranded DNA genomes, such as Ad, are sensed by the cell as damaged DNA which triggers a DDR. The DDR severely inhibits Ad DNA replication if unabated. Therefore, Ad has evolved multiple mechanisms to inhibit the DDR. The Ad E4-ORF3 protein relocalizes and sequesters proteins involved in a DDR into nuclear inclusions. Our research focuses on how the E4-ORF3 protein functions in this process. We found that E4-ORF3 induces the post-translational modification of cellular proteins involved in the DDR and other processes by SUMO (small ubiquitin-like modifier). We are studying how and why E4-ORF3 induces protein SUMO modification, and using proteomic approaches to identify novel targets of E4-ORF3-induced SUMO modification. Current results link these processes to a novel mechanism of protein degradation. Selected recent references. Sohn, S.Y. and Hearing, P. (2019) Mechanism of adenovirus E4-ORF3-mediated SUMO modification. MBio 10:e00022-19 (2019). doi: 10.1128/mBio.00022-19. Ostapchuk,P., Suomalainen,M., Zheng,Y., Boucke, K., Greber,U.F., and Hearing, P. (2017). The adenovirus major core protein VII is dispensable for virion assembly but is essential for lytic infection. PLoS Pathog. 13:e1006455 (2017). PMCID: PMC5491326. Zheng, Y., Stamminger, T. and Hearing, P. (2016). E2F/Rb family proteins mediate interferon induced repression of adenovirus immediate early transcription to promote persistent viral infection. PLoS Pathogens, e1005415. PMCID: PMC4726734 Sohn, S.Y., and Hearing, P. (2016). The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1γ sumoylation and poly-SUMO chain elongation. Proc. Natl. Acad. Sci. USA 113:6725-6730. PMCID: PMC4914182 Bridges, R.G., Sohn, S.Y., Wright, J., Leppard, K.N. and Hearing, P. The adenovirus E4-ORF3 protein stimulates SUMOylation of general transcription factor TFII-I to direct proteasomal degradation. MBio. 7:e02184-15 (2016). PMCID: PMC4742714
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