Genetics, Epigenetics & Gene Regulation | Immunology & Pathogens | Molecular Cell Biology
Signaling and gene expression in inflammation
Defense against infections requires efficient activation of an inflammatory response and timely reestablishment of immune homeostasis once the pathogen has been eradicated. Unproductive responses result in infectious disease whereas failures in homeostatic processes cause tissue damage and prevent healing. We study the molecular wiring of robust yet controlled inflammation at the level of transcription, mRNA decay and signaling...more
Defense against infections requires efficient activation of an inflammatory response and timely reestablishment of immune homeostasis once the pathogen has been eradicated. Unproductive responses result in infectious disease whereas failures in homeostatic processes cause tissue damage and prevent healing. We study the molecular wiring of robust yet controlled inflammation at the level of transcription, mRNA decay and signaling.
Defense against bacterial pathogens: Aurea mediocritas
Successful host defense requires precisely balanced immune responses to ensure pathogen clearance, while limiting exaggerated inflammation and tissue destruction. In models of invasive infection with pathogenic bacteria such as Streptococcus pyogenes we investigate the mechanisms of efficient activation of the immune system as well as the molecular principles of timely return into immune and tissue homeostasis. Our recent study (Castiglia et al., Cell Host & Microbe 2016) describes that activation of type I interferon (IFN) signaling in the context of Streptococcus pyogenes infection balances the immune response by ensuring that the production of the important pro-inflammatory cytokine IL-1ß reaches protective yet not destructive levels. This function of type I IFNs is essential for preventing lethal systemic hyperinflammation.
Regulation of immune homeostasis by mRNA decay
A considerable proportion of genes induced during inflammation are strongly regulated at the level of mRNA stability. The mRNA-destabilizing protein tristetraprolin (TTP, encoded by Zfp36) is a key factor regulating the elimination of mRNA of inflammatory proteins (e.g. cytokines). We investigate the function of TTP in the maintenance of immune homeostasis and its reestablishment after an insult. Our current study (Sedlyarov et al., Mol Syst Biol 2016) demonstrates that TTP is essential for the initiation of the resolution phase of inflammation. Failures in this TTP-mediated switch result in a constant firing of the immune system. By using PAR-iCLIP, a genome wide high-resolution mapping of TTP binding sites, in the transcriptome of immunostimulated primary mouse macrophages the study establishes a complete map of cis-acting elements controlling mRNA stability during inflammation. The binding sites are functionally annotated and publically accessible via the TTP Atlas webpage, a user friendly tool generated by Vitaly Sedlyarov and Florian Ebner.
Regulation of the transcription cycle in cytokine responses
Transcription is regulated at multiple steps in order to precisely adjust the transcriptional output to the internal and external cues. One of the key questions among the many still unresolved aspects of transcription regulation is the mechanism which prevents uncontrolled repetition of the transcription cycle once the upstream signal has vanished. This is of particular importance for avoiding exaggerated immune responses.
We have recently described a novel way of transcription control in the JAK-STAT signaling pathway: processive transcription initiated by STAT1 feeds back to downregulate promoter occupancy of STAT1 and, consequently, limit the transcription output (Wiesauer et al., Mol Cell Biol 2016). Our current data suggest that chromatin-associated signaling acts in cis to allow cross talk between promoter-bound transcription factor(s) and the transcritpion machinery. We have previously described that the CDK8 submodule of the Mediator complex is the key factor regulating the activity of STAT1 and other STAT family members in a chromatin-associated manner (Bancerek et al., Immunity 2013).
Castiglia, Virginia; Piersigilli, Alessandra; Ebner, Florian; Janos, Marton; Goldmann, Oliver; Damböck, Ursula; Kröger, Andrea; Weiss, Sigfried; Knapp, Sylvia; Jamieson, Amanda M; Kirschning, Carsten; Kalinke, Ulrich; Strobl, Birgit; Müller, Mathias; Stoiber, Dagmar; Lienenklaus, Stefan; Kovarik, Pavel (2016). Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue. Cell Host Microbe;19(3):375-87. PMID: 26962946
Sedlyarov, Vitaly; Fallmann, Jörg; Ebner, Florian; Huemer, Jakob; Sneezum, Lucy; Ivin, Masa; Kreiner, Kristina; Tanzer, Andrea; Vogl, Claus; Hofacker, Ivo; Kovarik, Pavel (2016). Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution. MOL SYST BIOL;12(5):868. PMID: 27178967
Bancerek, Joanna; Poss, Zachary C; Steinparzer, Iris; Sedlyarov, Vitaly; Pfaffenwimmer, Thaddäus; Mikulic, Ivana; Dölken, Lars; Strobl, Birgit; Müller, Mathias; Taatjes, Dylan J; Kovarik, Pavel (2013). CDK8 Kinase Phosphorylates Transcription Factor STAT1 to Selectively Regulate the Interferon Response. IMMUNITY:250-62. PMID: 23352233
Marie Curie ITN INBIONET
The lab participates in the EU FP7-funded Marie Curie Initial Training Network INBIONET
FWF stand alone grant "Function of CDK8 in STAT1-Regulated Transcription and Cytokine Responses"
Jakob Huemer; Master’s student; publications with the lab
Clemens Gaumannmüller; Master’s student; publications with the lab
Klemens Pranz; student´s job
Laura Wandruszka; Master’s student
Marion Aberle; Technician; publications with the lab
Ursula Damböck; Master’s student; publications with the lab
Christina Fieber (Mühlbacher); PhD student; publications with the lab
Ivana Wiesauer (Mikulic); PhD student; publications with the lab
Maike Werning; student´s job
Joanna Bancerek, PhD student, Postdoc; publications with the lab
Kristina Kreiner; Master’s student; publications with the lab
Nina Gratz; Master’s student, PhD student, Postdoc; publications with the lab
Franz Kratochvill; PhD student, Postdoc; publications with the lab
David Mairhofer; Master’s student
Thaddäus Pfaffenwimmer; Master’s student; publications with the lab
Harald Hartweger; Master’s student; publications with the lab
Christian Machacek, Master’s student; publications with the lab
Iwona Sadzak; Master’s student, PhD student; publications with the lab
Barbara Schaljo; PhD student; publications with the lab
Josephine Grass; Master’s student
Irene Gattermeier; Master's student; publications with the lab
Ines Sauer; PhD student; publications with the lab
Melanie Schiff; Master’s student; publications with the lab
Lab retreat September 2015 in Prein an der Rax in the villa of Gustav Ammerer