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Behrens, G.* ; Edelmann, S.L. ; Raj, T.* ; Kronbeck, N.* ; Monecke, T.* ; Davydova, E.-O. ; Wong, E.H.* ; Kifinger, L. ; Giesert, F. ; Kirmaier, M.E.* ; Hohn, C.* ; de Jonge, L.S. ; Pisfil, M.G.* ; Fu, M.* ; Theurich, S.* ; Feske, S.* ; Kawakami, N.* ; Wurst, W. ; Niessing, D. ; Heissmeyer, V.

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

Nat. Immunol. 22, 1563-1576 (2021)
Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Helper T-cells; Messenger-rna Decay; Differentiation; Leads; Recognition; Suppresses; Expression; Cleavage; Element; Repress
ISSN (print) / ISBN 1529-2908
e-ISSN 1529-2916
Zeitschrift Nature Immunology
Quellenangaben Band: 22, Heft: 12, Seiten: 1563-1576 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Heidelberger Platz 3, Berlin, 14197, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Abteilung für Molekulare Immunregulation (AMIR)
Institute of Structural Biology (STB)
Institute of Developmental Genetics (IDG)
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)