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Gamm, Matthias von, 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, Tschoep, Matthias H., Friedel, Caroline C., Hauck, Stefanie M., Sattler, Michael, Geerlof, Arie, Hornung, Veit, Heissmeyer, Vigo, Schulz, Christian, Heikenwalder, Mathias and Glasmacher, Elke (2019): Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3. In: Journal of Experimental Medicine, Vol. 216, No. 7: pp. 1700-1723

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The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kappa B signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed Regnase-3-deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell-specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade, and regulate mRNAs, such as Zc3h12a (Regnase-1), in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.

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