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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)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
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
Begutachtungsstatus Peer reviewed
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)