1. Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.
- Author
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Behrens G, Edelmann SL, Raj T, Kronbeck N, Monecke T, Davydova E, Wong EH, Kifinger L, Giesert F, Kirmaier ME, Hohn C, de Jonge LS, Pisfil MG, Fu M, Theurich S, Feske S, Kawakami N, Wurst W, Niessing D, and Heissmeyer V
- Subjects
- Animals, Female, HEK293 Cells, HeLa Cells, Humans, Immunity, Humoral, Male, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Phenotype, Protein Binding, Repressor Proteins genetics, Ribonucleases genetics, Skin Neoplasms genetics, Skin Neoplasms immunology, Skin Neoplasms metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Microenvironment, Ubiquitin-Protein Ligases genetics, Mice, Autoimmunity, Cytotoxicity, Immunologic, Immunotherapy, Adoptive, Melanoma, Experimental therapy, Repressor Proteins metabolism, Ribonucleases metabolism, Skin Neoplasms therapy, T-Lymphocytes transplantation, Ubiquitin-Protein Ligases metabolism
- Abstract
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., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2021
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