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Genetically modifying the RNA-binding protein Regnase-1 reveals its critical role in Treg homeostasis and functions in vivo

ABSTRACT: Regnase-1 is a CCCH-type RNA-binding protein that degrades mRNA species via its ribonuclease activities to inhibit immune responses. But how and by what mechanisms Regnase-1 controls Foxp3+ Tregs in vivo remains poorly studied. Here we generated a conditional knock-in mouse in which a degradation-resistant Regnase-1 mutant (R111A) was selectively expressed in Foxp3+ Tregs as a transgene (Foxp3YFP-CreLSL-R111Afl/fl) to investigate the roles of Regnase-1 in Tregs. We found that all male Foxp3YFP-CreLSL-R111Afl/fl mice died of fatal autoimmune diseases by 4 weeks of age, which was accompanied by massive activation of T effector cells in vivo. We also found that the Foxp3+ Tregs in male Foxp3YFP-CreLSL-R111Afl/fl mice were depleted in the periphery, but not Tregs in the thymus. Further analyses revealed that the Foxp3+ Tregs expressing the Regnase-1 mutant R111A displayed an intrinsic survival defect and that transferring wild type Foxp3+ Tregs into the young male Foxp3YFP-CreLSL-R111Afl/fl mice could rescue the lethal autoimmune phenotype. Mechanistically, we demonstrated that the Regnase-1 readily degraded Bcl2l1 mRNA (encoding Bcl-xL) via binding to its stem loop structure, thus preventing Bcl-xL expression in Tregs. Consequently, Tregs expressing the Regnase-1 mutant R111A exhibited not only survival defects but also failure to respond to IL-2 in vivo, thus leading to their eventual demise. Together, our studies suggest that Regnase-1 can have a profound impact on Foxp3+ Tregs and that modulating Regnase-1 in Tregs may have important therapeutic implications.

ORGANISM(S): Mus musculus

PROVIDER: GSE325328 | GEO | 2026/03/19

REPOSITORIES: GEO

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