Curt M. Horvath
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 are 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.
LGP2 synergy with MDA5 in RLR-mediated RNA recognition and antiviral signaling. Bruns AM and Horvath CM. Cytokine. 2015 August;74(2):198-206.
Pan-cancer analysis of TCGA data reveals notable signaling pathways. Neapolitan R, Horvath CM, and Jiang X. BMC Cancer. 2015 July 14;15:516.
Antiviral RNA recognition and assembly by RLR family innate immune sensors. Bruns AM and Horvath CM. Cytokine & Growth Factor Reviews. 2014 October;25(5):507-512.
The Innate Immune Sensor LGP2 Activates Antiviral Signaling by Regulating MDA5-RNA Interaction and Filament Assembly. Bruns AM, Leser GP, Lamb RA, and Horvath CM. Molecular Cell. 2014 September 4;55(5):771-781.
High-Density Nucleosome Occupancy Map of Human Chromosome 9p21–22 Reveals Chromatin Organization of the Type I Interferon Gene Cluster. Freaney JE, Zhang Q, Yigit E, Kim R, Widom J, Wang J-P, and Horvath CM. Journal of Interferon & Cytokine Research. 2014 September 2;34(9):676-685.
Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors. Tell RW and Horvath CM. PNAS. 2014 September 2;111(35):12787-12792.
MDA5 and LGP2: Accomplices and Antagonists of Antiviral Signal Transduction. Rodriguez KR, Bruns AM, and Horvath CM. Journal of Virology. 2014 August;88(15):8194-8200.
Paramyxovirus V Protein Interaction with the Antiviral Sensor LGP2 Disrupts MDA5 Signaling Enhancement but Is Not Relevant to LGP2-Mediated RLR Signaling Inhibition. Rodriguez KR and Horvath CM. Journal of Virology. 2014 July;88(14):8180-8188.
Small RNA Profiling of Influenza A Virus-Infected Cells Identifies miR-449b as a Regulator of Histone Deacetylase 1 and Interferon Beta. Buggele WA, Krause KE, and Horvath CM. PLoS ONE. 2013 September 26;8(9):e76560.
Extensive Cooperation of Immune Master Regulators IRF3 and NFκB in RNA Pol II Recruitment and Pause Release in Human Innate Antiviral Transcription. Freaney JE, Kim R, Mandhana R, and Horvath CM. Cell Reports. 2013 September 12;4(5):959-973.
MicroRNA Profiling of Sendai Virus-Infected A549 Cells Identifies miR-203 as an Interferon-Inducible Regulator of IFIT1/ISG56. Buggele WA and Horvath CM. Journal of Virology. 2013 August;87(16):9260-9270.
Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway. Au-Yeung N, Mandhana R, and Horvath CM. JAK-STAT. 2013 July;2(3):e23931.
A Conserved Role for Human Nup98 in Altering Chromatin Structure and Promoting Epigenetic Transcriptional Memory. Light WH, Freaney J, Sood V, Thompson A, D’Urso A, Horvath CM, and Brickner JH. PLoS Biology. 2013 March 26;11(3):e1001524.
Amino Acid Requirements for MDA5 and LGP2 Recognition by Paramyxovirus V Proteins: a Single Arginine Distinguishes MDA5 from RIG-I. Rodriguez KR and Horvath CM. Journal of Virology. 2013 March;87(5):2974-2978.
ATP Hydrolysis Enhances RNA Recognition and Antiviral Signal Transduction by the Innate Immune Sensor, Laboratory of Genetics and Physiology 2 (LGP2). Bruns AM, Pollpeter D, Hadizadeh N, Myong S, Marko JF, and Horvath CM. Journal of Biological Chemistry. 2013 January 11;288(2):938-946.
View all publications by Curt M. Horvath listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.