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.
Highlights
Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins
We find that EAE severity is attenuated in Hectd3−/− mice, which correlates with diminished IL-17A and GM-CSF production, RORγt levels, and reduced phosphorylated (p)Stat[3] Y705 in Hectd3−/− CD4+ T cells
Given the overall reduction in T helper 17 (Th17) program, including cytokines and the pathogenicity marker IL-23R, all known to be transcriptionally regulated by RORγt[11,13,17,39], we evaluated the level of the Th17 transcription factor RORγt in CNS-infiltrating and draining lymph nodes (dLNs) CD4+ T cells from Hectd3−/− mice during EAE
Summary
Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Stat[3] K180 and Malt[1] K648 are targeted by Hectd[3] for non-degradative polyubiquitination to mediate robust generation of RORγt+IL-17Ahi effector CD4+ T cells. Our studies delineate a mechanism connecting signaling related polyubiquitination of Malt[1] and Stat[3], leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE. IL-6 signaling engenders phosphorylation and activation of Stat[3], which is another key transcription factor in Th17 cell differentiation[13,14,15]. In MS and its mouse model EAE2,18,19, IL-23R signaling drives the co-expression of the highly pro-inflammatory cytokines GM-CSF and IFNγ through RORγt, activated Stat[3], and Blimp-117–20.
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