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Regulation of nucleic acid recognition by nucleases and metabolism

Effect of pyroptosis on nucleic acid metabolism and immune sensing (A06)

 

TR_A06.4

Project Ieader: Dr. Eva Bartok

 

The discrimination between physiological and pathological forms of cell death is critical to an appropriate immune response. In our preliminary work, we observed that pyroptotic cell death renders cellular corpses and their DNA immunostimulatory. Moreover, our data demonstrate that this effect is critically dependent on the presence of both the lysosomal endonuclease DNase II in pyroptotic cells and of cytosolic Three prime Repair Exonuclease 1 (TREX1) in recipient phagocytes: DNase II generates 3´-monophosphate termini (3’P DNA), rendering DNA resistant to degradation by TREX1. In this project, we aim to expand on these initial findings and investigate how this effect contributes to the recognition of intracellular pathogens during pyroptosis. In addition, we will investigate the role of the endogenous 3’ phosphatase PNKP in controlling these responses. 


Degradation of viral or immunostimulatory RNA in infected cells (A07) 

 

TR_A07.4

Project Ieader: Prof. Andreas Pichlmair 

 

The successful elimination of viral infections requires the targeting and degradation of viral nucleic acids. Surprisingly little is known regarding molecular mechanisms that are specifically targeting viral RNA and yet do not affect cellular RNA such as messenger, ribosomal or transfer RNA. This proposal aims at elucidating the half-life of viral nucleic acid and the functional characterization of pathways and proteins that are involved in this process. We anticipate that this knowledge will allow us to gain insights into the successful elimination of viruses and in physiological processes that aim to remove stimulatory RNA under steady state conditions.


Molecular mechanisms of Superkiller-like helicases (A08)

 

TR_A08.4

Project Ieader: Prof. Elena Conti 

 

Increasing evidence implicates the RNA exosome, a major complex in cellular RNA decay mechanisms, as a player in viral immunity and autoimmunity. The RNA exosome is a powerful RNA-degrading machine, but in itself lacks specificity. Superkiller-like helicases are believed to assist the exosome by recognizing specific RNAs and targeting them for degradation, but the molecular mechanisms are poorly understood. In this project, we will study Superkiller-like helicases that have been linked to the regulation of RIG-I-like receptors, aiming to understand how they function at the molecular level and the basis for their malfunction in disease mutants.


Molecular and cellular characterization of the nuclease TREX2 (J01)

 

TR_J01.1

Project Ieader: Dr. Christine Wolf

 

Nucleolytic degradation of RNA and DNA plays an important role in the regulation of innate immune responses, as erroneous immune recognition of self nucleic acids can cause type I IFN-dependent autoinflammation and autoimmunity. Three prime repair exonuclease 2 (TREX2) is a 3′→5′ exonuclease, which shares structural and enzymatic properties with the DNase TREX1, mutations of which cause type I IFN-driven disease. In contrast to TREX1, which acts in the cytosol, TREX2 resides in the nucleus. While TREX2 has been suggested to be involved in DNA repair, its biological function and its potential role in type I IFN-dependent innate immunity remains largely unknown. The aim of this study is to understand the functions of TREX2 in normal cell physiology by dissecting its molecular and cellular properties and the biological processes regulated by TREX2.


 

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