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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
Schlagwörter Helper T-cells; Messenger-rna Decay; Differentiation; Leads; Recognition; Suppresses; Expression; Cleavage; Element; Repress
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
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
Institut(e) Research Unit Molecular Immune Regulation (AMIR)
Institute of Structural Biology (STB)
Institute of Developmental Genetics (IDG)
POF Topic(s) 30203 - Molecular Targets and Therapies
30204 - Cell Programming and Repair
Forschungsfeld(er) Immune Response and Infection
Enabling and Novel Technologies
Genetics and Epidemiology
PSP-Element(e) G-501712-001
G-503091-001
G-500500-001
G-500500-009
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)
DOI 10.1038/s41590-021-01064-3
WOS ID WOS:000726155500015
WOS ID WOS:000722315400008
Scopus ID 85119661583
PubMed ID 34811541
Erfassungsdatum 2021-12-21
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