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

Jonathan J. Cho, Zhiwei Xu, Upasana Parthasarathy, Theodore T. Drashansky, Eric Y. Helm, Ashley N. Zuniga, Kyle J. Lorentsen, Samira Mansouri, Joshua Y. Cho, Mariola J. Edelmann, Duc M. Duong, Torben Gehring, Thomas Seeholzer, Daniel Krappmann, Mohammad N. Uddin, Danielle Califano, Rejean L. Wang, Lei Jin, Hongmin Li, Dongwen Lv, Daohong Zhou, Liang Zhou and Dorina Avram ()
Additional contact information
Jonathan J. Cho: College of Medicine, University of Florida
Zhiwei Xu: College of Medicine, University of Florida
Upasana Parthasarathy: College of Medicine, University of Florida
Theodore T. Drashansky: College of Medicine, University of Florida
Eric Y. Helm: College of Medicine, University of Florida
Ashley N. Zuniga: College of Medicine, University of Florida
Kyle J. Lorentsen: University of Florida
Samira Mansouri: University of Florida
Joshua Y. Cho: University of Florida
Mariola J. Edelmann: University of Florida
Duc M. Duong: Emory University School of Medicine
Torben Gehring: Helmholtz Zentrum München - German Research Center for Environmental Health
Thomas Seeholzer: Helmholtz Zentrum München - German Research Center for Environmental Health
Daniel Krappmann: Helmholtz Zentrum München - German Research Center for Environmental Health
Mohammad N. Uddin: Albany Medical Center
Danielle Califano: Albany Medical Center
Rejean L. Wang: University of Florida
Lei Jin: University of Florida
Hongmin Li: New York State Department of Health
Dongwen Lv: University of Florida
Daohong Zhou: University of Florida
Liang Zhou: University of Florida
Dorina Avram: College of Medicine, University of Florida

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract 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 RORγt, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-κB 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 RORγt+IL-17Ahi effector CD4+ T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE.

Date: 2019
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DOI: 10.1038/s41467-019-08605-3

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