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Cho, J.J.* ; Xu, Z.* ; Parthasarathy, U.* ; Drashansky, T.T.* ; Helm, E.Y.* ; Zuniga, A.N.* ; Lorentsen, K.J.* ; Mansouri, S.* ; Cho, J.Y.* ; Edelmann, M.J.* ; Duong, D.M.* ; Gehring, T. ; Seeholzer, T. ; Krappmann, D. ; Uddin, M.N.* ; Califano, D.* ; Wang, R.L.* ; Jin, L.* ; Li, H.* ; Lv, D.* ; Zhou, D.* ; Zhou, L.* ; Avram, D.*

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation.

Nat. Commun. 10:701 (2019)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not ROR gamma t, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-kappa B activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of ROR gamma t+ IL-17A(hi) effector CD4(+) T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and ROR gamma t expression, to pathogenic Th17 cell function in EAE.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ror-gamma-t; Nf-kappa-b; Growth-factor-beta; Paracaspase Malt1; T-h-17 Cells; Interleukin-17 Production; Gene-expression; T(h)17 Cells; Ubiquitin; Receptor
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 10, Heft: 1, Seiten: , Artikelnummer: 701 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)