Was ist die Funktion von Regnase-3, einem neuem Post-transkriptionellem Regulator, in Immunantworten?
Zellbiologie
Zusammenfassung der Projektergebnisse
The DFG grant was funded to identify the role of Regnase-3 for immune responses and its mode of action. Therefore, we analyzed Regnase-3-deficient mice, which develop hypertrophic lymph nodes. To do so, we used various mice with immune cell-specific deletions of Regnase-3 and demonstrated that Regnase-3 acts specifically within myeloid cells. We showed with immunohistochemistry, FACS analysis and Sequencing approaches that Regnase-3 deficiency systemically increased IFN signaling. This then resulted in an increase of immature B and innate immune cells in lymph nodes and suppressed follicle and germinal center formation. We generated our own Regnase-3-specific antibody, which allowed us to perform expression and localization analysis using primary immune cells. This revealed that Regnase-3 and Regnase-1 actually do share protein degradation pathways. Nevertheless, unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although we had extreme difficulties to identify the direct targets in macrophages, which still remain unknown, we demonstrated that Regnase-3 can bind, degrade, and regulate mRNAs, such as Zc3h12a (Regnase-1), in vitro. Finally, we unmasked Regnase-3, like Regnase- 1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.
Projektbezogene Publikationen (Auswahl)
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Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3. J Exp Med. 2019 Jul 1;216(7):1700-1723
von Gamm, Matthias; Schaub, Annalisa; Jones, Alisha N.; Wolf, Christine; Behrens, Gesine; Lichti, Johannes; Essig, Katharina; Macht, Anna; Pircher, Joachim; Ehrlich, Andreas; Davari, Kathrin; Chauhan, Dhruv; Busch, Benjamin; Wurst, Wolfgang; Feederle, Regina; Feuchtinger, Annette; Tschöp, Matthias H.; Friedel, Caroline C.; Hauck, Stefanie M.; ... & Glasmacher, Elke
