Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses
| Autor: | Stephanie L. Edelmann, Laura S. de Jonge, Lisa Kifinger, Wolfgang Wurst, Florian Giesert, Christine Hohn, Naoto Kawakami, Sebastian Theurich, Mingui Fu, Dierk Niessing, Nina Kronbeck, Martin E. Kirmaier, Vigo Heissmeyer, Timsse Raj, Thomas Monecke, Elena S. Davydova, Elaine H. Wong, Stefan Feske, Gesine Behrens, Mariano Gonzalez Pisfil |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cytotoxicity
Immunologic Male Skin Neoplasms T-Lymphocytes Melanoma Experimental Autoimmunity medicine.disease_cause Zc3h12a protein mouse Immunotherapy Adoptive immunology [T-Lymphocytes] Tumor Microenvironment Immunology and Allergy genetics [Ribonucleases] metabolism [Repressor Proteins] genetics [Ubiquitin-Protein Ligases] Mutation therapy [Skin Neoplasms] transplantation [T-Lymphocytes] metabolism [Skin Neoplasms] Cell biology medicine.anatomical_structure therapy [Melanoma Experimental] Phenotype Female Protein Binding T cell Ubiquitin-Protein Ligases Immunology Mice Transgenic Biology immunology [Melanoma Experimental] Article Proinflammatory cytokine genetics [Skin Neoplasms] Immune system metabolism [Ubiquitin-Protein Ligases] Ribonucleases medicine Animals Humans ddc:610 metabolism [T-Lymphocytes] Autoantibody genetics [Melanoma Experimental] Germinal center Immunity Humoral Mice Inbred C57BL Repressor Proteins genetics [Repressor Proteins] HEK293 Cells immunology [Skin Neoplasms] Rc3h1 protein mouse metabolism [Melanoma Experimental] metabolism [Ribonucleases] roquin-2 protein mouse CD8 HeLa Cells |
| Zdroj: | Nat Immunol Nat. Immunol. 22, 1563-1576 (2021) Nature immunology 22(12), 1563-1576 (2021). doi:10.1038/s41590-021-01064-3 |
| Popis: | 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. Mutations in the RNA-binding proteins Roquin-1 or Regnase-1 cause systemic autoimmunity. Heissmeyer and colleagues show that Roquin-1 and Regnase-1 physically interact and thereby regulate CD4+ and CD8+ T cell metabolism and functionality. |
| Databáze: | OpenAIRE |
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