Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses

Gesine Behrens, Stephanie L. Edelmann, Timsse Raj, Nina Kronbeck, Thomas Monecke, Elena Davydova, Elaine H. Wong, Lisa Kifinger, Florian Giesert, Martin E. Kirmaier, Christine Hohn, Laura S. de Jonge, Mariano Gonzalez Pisfil, Mingui Fu, Sebastian Theurich, Stefan Feske, Naoto Kawakami, Wolfgang Wurst, Dierk Niessing & Vigo Heissmeyer. Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses. Nat Immunol (2021). https://doi.org/10.1038/s41590-021-01064-3

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Abstract cited from the publication:

Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.