Signal transduction and gene regulation in innate immune responses to cancer and viruses

My laboratory studies how polypeptide signals, cytokines important for antiviral and antitumor immunity, specify alterations in gene expression patterns. Greater knowledge of these processes will lead to improved diagnostic tools and treatment options for many diseases resulting from defective cell signaling like cancer, immune dysfunction, and birth defects. We are particularly interested in the interactions between the antiviral immune system and viral pathogens.

The regulation of inducible transcriptional responses is being studied by focusing on transcription activating proteins involved in Interferon signaling called STATs (for Signal Transducers and Activators of Transcription) and IRFs (for Interferon Regulatory Factors). STATs become active as DNA-binding factors in response to cell surface receptor activation by the polypeptides and directly bind to the promoters of target genes. IRFs are constitutive DNA binding proteins with regulated subcellular distribution. Both families of proteins activate gene expression alone and in combination with other cellular proteins to give rise to a wide range of biological responses involved in innate and adaptive immune function.

Two major questions currently dominate the research in the lab. The first question is "How do STAT and IRF proteins function as transcription factors?" We have found several transcriptional co-activators that crucial for IFN responses and continue to investigate their role in gene regulation and chromatin remodeling. The second question is " How do viruses recognize and avoid IFN responses and STAT protein functions?". We have discovered a diverse range of STAT-directed IFN evasion mechanisms in the paramyxovirus family of RNA viruses, ranging from virus-induced ubiquitylation and degradation to cytoplasmic sequestration. The pursuit of both questions has resulted in many new and exciting research directions for future study in the areas of immune regulation, gene regulation, host-pathogen interactions, virology, and cell biology.

Komuro A, Horvath CM. RNA- and virus-independent inhibition of antiviral signaling by RNA helicase LGP2. J Virol. 2006 Dec;80(24):12332-42. Epub 2006 Oct 4.

Yount JS, Kraus TA, Horvath CM, Moran TM, Lopez CB. A novel role for viral-defective interfering particles in enhancing dendritic cell maturation. J Immunol. 2006 Oct 1;177(7):4503-13.

Cruz CD, Palosaari H, Parisien JP, Devaux P, Cattaneo R, Ouchi T, Horvath CM. Measles virus V protein inhibits p53 family member p73. J Virol. 2006 Jun;80(11):5644-50.

Gu W, Nusinzon I, Smith RD Jr, Horvath CM, Silverman RB. Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases. Bioorg Med Chem. 2006 May 15;14(10):3320-9. Epub 2006 Jan 24.

Nusinzon I, Horvath CM. Positive and negative regulation of the innate antiviral response and beta interferon gene expression by deacetylation. Mol Cell Biol. 2006 Apr;26(8):3106-13.

Horvath CM. Silencing STATs: Lessons from Paramyxovirus Interferon Evasion. For Cytokine and Growth Factor Reviews.

Rodriguez, JJ, Cruz CD, Horvath CM. Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion. J. Virology 2004;78(10):5358-5367.

Lau JF, Nusinzon I, Burakov D, Freedman LP, Horvath CM. Role of Metazoan Mediator Proteins in Interferon-Responsive Transcription. Mol Cell Biol 2003;23(2):620-628.

Kraus TA, Lau JF, Parisien JP, Horvath CM. A Hybrid IRF9-STAT2 Protein that Recapitulates Interferon Gene Expression and Biological Response. J Biol Chem 2003;278(15):13033-13038.

Ulane CM, Rodriguez JR, Parisien JP, Horvath CM. STAT3 Ubiquitylation and Degradation by Mumps Virus Suppress Cytokine and Oncogene Signaling. J Virology 2003;77(11):6385-6893.

Palosaari H, Parisien JP, Rodriguez JJ, Ulane CM, Horvath CM. STAT Protein Interference and Suppression of Cytokine Signal Transduction by Measles Virus V Protein. J Virology 2003;77(13):7635-7644.

Rodriguez JR, Wang LF, Horvath CM. Hendra Virus V protein inhibits IFN signaling by preventing STAT1 and STAT2 nuclear accumulation. J Virology 2003;77(21):11842-11845.

Nusinzon I, Horvath CM. Interferon-Stimulated Transcription and Innate Antiviral Immunity Require Deacetylase Activity and HDAC1. Proc Natl Acad Sci USA 2003; (in press).

Aaronson DS, Horvath CM. A Road Map for Those Who Don't Know JAK-STAT. Science 2002 May 31;296(5573):1653-1655

View all publications by publications by Curt M. Horvath listed in the National Library of Medicine (PubMed).