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Your search keyword '"Edelmann SL"' showing total 2 results
Start Over Author "Edelmann SL" Publisher nature america inc
2 results on '"Edelmann SL"'

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

Author

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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2. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.

Author

Jeltsch KM, Hu D, Brenner S, Zöller J, Heinz GA, Nagel D, Vogel KU, Rehage N, Warth SC, Edelmann SL, Gloury R, Martin N, Lohs C, Lech M, Stehklein JE, Geerlof A, Kremmer E, Weber A, Anders HJ, Schmitz I, Schmidt-Supprian M, Fu M, Holtmann H, Krappmann D, Ruland J, Kallies A, Heikenwalder M, and Heissmeyer V

Subjects
Adaptor Proteins, Signal Transducing genetics, Amino Acid Sequence, Animals, Binding Sites immunology, Cell Differentiation immunology, Cell Line, Genes, rel genetics, HEK293 Cells, Humans, Inducible T-Cell Co-Stimulator Protein genetics, Interferon Regulatory Factors genetics, Interleukin-6 genetics, Intracellular Signaling Peptides and Proteins, Lung immunology, Lung pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Nuclear Proteins genetics, Proteins genetics, RNA, Messenger genetics, RNA-Binding Proteins metabolism, Sequence Alignment, Th17 Cells immunology, Ubiquitin-Protein Ligases genetics, Caspases metabolism, Neoplasm Proteins metabolism, Receptors, Antigen, T-Cell immunology, Ribonucleases metabolism, Th17 Cells cytology, Ubiquitin-Protein Ligases metabolism
Abstract

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

Published
2014
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