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Patrick Hearing

Lab Members

Publications

 

 

 
Patrick Hearing

Professor

Ph.D., Northwestern University, 1980

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(631)632-8813
(631) 632-8891

   
Research

My laboratory studies the human DNA tumor virus adenovirus (Ad). Ad has proven to be an excellent model system to study the regulation of numerous cellular processes including proliferation,g ene expression, apoptosis, and host antiviral responses to infection. Recombinant Ad vectors also are promising agents for therapeutic gene delivery for both short term and long term treatment of a variety of inherited and acquired diseases. 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 viralr eplication program.

Adenovirus induction of an interferon (IFN) response.

The Ad DNA genome is sensed by cellular pattern recognition 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 IFNa and type II IFNg block wild-type Ad replication in primary human bronchial epithelial cells normal human diploid fibroblasts. IFNs inhibit viral gene expression and our studies are focused 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. We wish to study this process in primary human T calls, a natutal reservoir for persistent Ad infection.

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 sequester nuclear proteins involved in a DDR into nuclear inclusions termed tracks (see figure). Our research focuses on how the E4-ORF3 protein functions in this process. We found that E4-ORF3 induces the post-translational modification of proteins involved in the DDR 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.

Bridges, R.G., Sohn, S.Y., Wright, J, Leppard, K.N. and Hearing, P. (2016). The adenovirus E4-ORF3 protein stimulates SUMOylation of general transcription factor TFII-I to direct proteasomal degradation. mBio, e02184-15.

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.

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.

Department of Molecular Genetics and Microbiology
Stony Brook University
Stony Brook, New York 11794-5222
Phone: 631-632-8800
Fax: 631-632-9797

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