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Gewies, A.* ; Gorka, O.* ; Bergmann, H.* ; Pechloff, K.* ; Petermann, F.* ; Jeltsch, K. ; Rudelius, M.* ; Kriegsmann, M.* ; Weichert, W.* ; Horsch, M. ; Beckers, J. ; Wurst, W. ; Heikenwälder, M. ; Korn, T.* ; Heissmeyer, V. ; Ruland, J.*

Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.

Cell Rep. 9, 1292-1305 (2014)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 9, Heft: 4, Seiten: 1292-1305 Artikelnummer: , Supplement: ,
Verlag Cell Press
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Institute of Molecular Immunology (IMI)
Institute of Virology (VIRO)
Institute of Developmental Genetics (IDG)
POF Topic(s) 30201 - Metabolic Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
Immune Response and Infection
PSP-Element(e) G-500600-004
G-501792-001
G-551600-001
G-500500-001
PubMed ID 25456129
DOI 10.1016/j.celrep.2014.10.044
WOS ID WOS:000345529600014
Scopus ID 84912110913
Erfassungsdatum 2014-11-21
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