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; Dorina Avram

doi:10.1038/s41467-019-08605-3

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 LvDaohong Zhou, Liang Zhou, Dorina Avram

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56 Scopus citations

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-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 RORγt expression, to pathogenic Th17 cell function in EAE.

Original language	English (US)
Article number	701
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08605-3
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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., ... Avram, D. (2019). Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation. Nature communications, 10(1), Article 701. https://doi.org/10.1038/s41467-019-08605-3

Cho, JJ, Xu, Z, Parthasarathy, U, Drashansky, TT, Helm, EY, Zuniga, AN, Lorentsen, KJ, Mansouri, S, Cho, JY, Edelmann, MJ, Duong, DM, Gehring, T, Seeholzer, T, Krappmann, D, Uddin, MN, Califano, D, Wang, RL, Jin, L, Li, H, Lv, D, Zhou, D, Zhou, L & Avram, D 2019, 'Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation', Nature communications, vol. 10, no. 1, 701. https://doi.org/10.1038/s41467-019-08605-3

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title = "Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation",

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-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 RORγt expression, to pathogenic Th17 cell function in EAE.",

author = "Cho, {Jonathan J.} and Zhiwei Xu and Upasana Parthasarathy and Drashansky, {Theodore T.} and Helm, {Eric Y.} and Zuniga, {Ashley N.} and Lorentsen, {Kyle J.} and Samira Mansouri and Cho, {Joshua Y.} and Edelmann, {Mariola J.} and Duong, {Duc M.} and Torben Gehring and Thomas Seeholzer and Daniel Krappmann and Uddin, {Mohammad N.} and Danielle Califano and Wang, {Rejean L.} and Lei Jin and Hongmin Li and Dongwen Lv and Daohong Zhou and Liang Zhou and Dorina Avram",

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doi = "10.1038/s41467-019-08605-3",

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AU - Cho, Jonathan J.

AU - Xu, Zhiwei

AU - Parthasarathy, Upasana

AU - Drashansky, Theodore T.

AU - Helm, Eric Y.

AU - Zuniga, Ashley N.

AU - Lorentsen, Kyle J.

AU - Mansouri, Samira

AU - Cho, Joshua Y.

AU - Edelmann, Mariola J.

AU - Duong, Duc M.

AU - Gehring, Torben

AU - Seeholzer, Thomas

AU - Krappmann, Daniel

AU - Uddin, Mohammad N.

AU - Califano, Danielle

AU - Wang, Rejean L.

AU - Jin, Lei

AU - Li, Hongmin

AU - Lv, Dongwen

AU - Zhou, Daohong

AU - Zhou, Liang

AU - Avram, Dorina

PY - 2019/12/1

Y1 - 2019/12/1

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

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