Innate Immunology; Intracellular Signaling Pathways; Gap junction communication
Ablasser Andrea, Hur Sun (2020), Regulation of cGAS- and RLR-mediated immunity to nucleic acids, in Nature Immunology
, 21(1), 17-29.
Ablasser Andrea, Chen Zhijian J. (2019), cGAS in action: Expanding roles in immunity and inflammation, in Science
, 363(6431), eaat8657-eaat8657.
Haag Simone M., Gulen Muhammet F., Reymond Luc, Gibelin Antoine, Abrami Laurence, Decout Alexiane, Heymann Michael, van der Goot F. Gisou, Turcatti Gerardo, Behrendt Rayk, Ablasser Andrea (2018), Targeting STING with covalent small-molecule inhibitors, in Nature
, 559(7713), 269-273.
Gulen Muhammet F., Koch Ute, Haag Simone M., Schuler Fabian, Apetoh Lionel, Villunger Andreas, Radtke Freddy, Ablasser Andrea (2017), Signalling strength determines proapoptotic functions of STING, in Nature Communications
, 8(1), 427-427.
, Innate Immune Sensing of Cytosolic Chromatin Fragments Through cGAS Promotes Senescence, in Nature Cell Biology
The innate immune response of multicellular organisms relies on the extraordinary capability of cells to collaborate via cell-to-cell communication. The coordination of cellular collaboration is primarily attributed to cytokines and chemokines, which are being secreted by pathogen-infected cells. Cytokines, such as type I interferons (IFNs), can alert non-infected cells to anticipate pathogen challenge through paracrine signaling. Moreover, cytokines serve to instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signaling pathways have been identified that connect pathogen sensing with the production of cytokines, with the cytosolic sensing of nucleic acids being exquisitely important for the activation of type I IFNs. Intracellular DNA is sensed by the nucleotidyltransferase cGAS, which catalyzes the synthesis of the 2nd messenger cGAMP. This molecule in turn activates the ER-resident receptor STING to induce the transcriptional up-regulation of type I IFNs and to promote an antiviral state. Recently, we have identified a novel mechanism, whereby antiviral immunity is transferred to non-infected cells in the absence paracrine signaling. Specifically, we have demonstrated that upon DNA sensing cGAS-produced cGAMP shuttles to bystander cells, where it confers antiviral immunity in a STING-dependent manner. We hypothesize that this particular route of intercellular communication serves an important role in antimicrobial immunity and we speculate that similar concepts apply to other pattern recognition receptor (PRR) signaling pathways. The goals of this proposal are to address the functional relevance of horizontal cGAMP transfer during DNA-virus infection and to characterize novel host factors involved in the regulation of this mechanism. We will also screen additional PRR-systems for their capability to regulate innate immune responses by mechanisms relying on gap junction communication. A detailed knowledge of PRR-triggered intercellular signalling mechanisms will not only be a critical step towards a global understanding of the innate immune response to pathogens but could also provide novel concepts for the treatment of infectious diseases.