title: Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.
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.
authors.affiliation: 1] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Jeltsch
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Desheng
authors.initials: D
authors.lastname: Hu
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Sven
authors.identifier: 0000000157713907
authors.initials: S
authors.lastname: Brenner
authors.affiliation: Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zöller
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Gitta A
authors.initials: GA
authors.lastname: Heinz
authors.affiliation: Institute of Toxicology and Pharmacology, Research Unit Cellular Signal Integration, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nagel
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Katharina U
authors.initials: KU
authors.lastname: Vogel
authors.affiliation: 1] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Rehage
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Warth
authors.affiliation: 1] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Edelmann
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Gloury
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Martin
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lohs
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Stehklein
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Arie
authors.initials: A
authors.lastname: Geerlof
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Institute for Surgical Pathology, University Hospital, Zürich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: 1] Helmholtz Centre for Infection Research, Braunschweig, Germany. [2] Institute for Molecular and Clinical Immunology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
authors.forename: Ingo
authors.identifier: 0000000253600419
authors.initials: I
authors.lastname: Schmitz
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Holtmann
authors.affiliation: Institute of Toxicology and Pharmacology, Research Unit Cellular Signal Integration, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: 1] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D020573:Genes, rel / Q000235:genetics; D057809:HEK293 Cells; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012260:Ribonucleases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D016415:Sequence Alignment; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020169:Caspases; D060889:Inducible T-Cell Co-Stimulator Protein; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D012260:Ribonucleases; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4; C556694:Icos protein, mouse; C454819:Nfkbid protein, mouse; C498509:Malt1 protein, mouse; C485947:Nfkbiz protein, mouse; C501406:Rc3h1 protein, mouse; C541320:Zc3h12a protein, mouse