Host-mediated ubiquitination of a mycobacterial protein suppresses immunity

Wang, Lin; Wu, Juehui; Li, Jun; Yang, Hua; Tang, Tianqi; Liang, Haijiao; Zuo, Mianyong; Wang, Jie; Liu, Haipeng; Liu, Feng; Chen, Jianxia; Z, Liu; Wang, Yang; Peng, Cheng; Wu, Xiangyang; Zheng, Ruijuan; Huang, Xiaochen; Ran, Yajun; Rao, Zihe; Ge, Baoxue

doi:10.1038/s41586-019-1915-7

Cited by 69 publications

(74 citation statements)

References 31 publications

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“…Although APC/C E3 ligase is a complex with multiple subunits, overexpression of APC2 alone was reported to promote the ubiquitination of substrates. 71,72 In our study, overexpression of APC2 promoted the ubiquitination of DOK7, suggesting that other APC/C subunits might be also expressed. Indeed, we found that there are APC2 and other core subunits in the diaphragm of P0 mice ( Figure S3).…”

Section: Discussionsupporting

confidence: 55%

APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

et al. 2020

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Neuromuscular junctions (NMJs) are peripheral synapses between motoneurons and skeletal muscle fibers that are critical for the control of muscle contraction. Dysfunction of these synapses has been implicated in congenital myasthenic syndrome (CMS). In vertebrates, agrin‐LRP4‐MuSK signaling plays a critical role in acetylcholine receptor (AChR) clustering and NMJ formation. The adaptor protein DOK7 is the downstream substrate of MuSK and also a cytoplasmic activator of MuSK. The role of DOK7 in the promotion of AChR clustering and the mechanisms involved have been well studied; however, the negative regulation of DOK7 after MuSK activation remains unknown. Anaphase‐promoting complex 2 (APC2), the core subunit of APC/C E3 ligase complex, was originally believed to regulate cell‐cycle transitions. Here, we show that APC2 is enriched at post‐synapse of NMJs in postmitotic myotubes. In response to agrin stimulation, APC2 negatively regulates AChR clustering by promoting the ubiquitination of DOK7 at lysine 243 for its proteolytic degradation, which relies on MuSK kinase activity and the phosphorylation of tyrosine 106 in DOK7. Thus, this study provides a mechanism whereby agrin signaling is negatively regulated as part of vertebrate NMJ homeostasis.

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Section: Discussionsupporting

confidence: 55%

APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

et al. 2020

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“…If USP15 was knocked out, ERK2 would undergo more ubiquitination modi cations. The most common role in ubiquitination is protein degradation [40][41][42]. Surprisingly, even though USP15 could deubiquitinate ERK2, the degradation of endogenous ERK2 was not changed by USP15.…”

Section: Discussionmentioning

confidence: 99%

Positive Feedback Regulation between USP15 and ERK2 Promotes Cartilage Repair Through the TGF-β/SMAD2 signaling

Wang

Zhu

Sun

et al. 2020

Preprint

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The transforming growth factor-β (TGF-β) signaling pathway plays an essential role in maintaining homeostasis in joints affected by osteoarthritis (OA). Here, we detected that overexpression of USP15, rather than USP15 C269S (a USP15 mutant), activated p-SMAD2 in ATDC5 cells, which also went down by USP15 knocked out followed by the latest gene editing technology Crispr/Cas9. And we established rat knee OA models through anterior cruciate ligament transection and partial medial meniscectomy (ACLT+pMMx) after 8 weeks and conducted the corresponding Adeno-associated virus (AAV) intraarticular injections. Next, experimental data including immunohistochemical staining, HE/Safranin-O fast green staining, histological evidence analysis, relevant Osteoarthritis Research Society International (OARSI) scores, expression of molecules involved in cartilage anabolism and so on indicated that USP15 can reduce damaged cartilage by activating TGF-β signaling pathway in vivo. We further observed that ERK2 of non-SMAD signaling can maintain the cartilage phenotype by regulating the TGF-β signaling pathway through USP15 in vitro and in vivo. Most importantly, USP15 is required during this process and can form a complex with ERK2 to regulate ubiquitination of ERK2. Specifically, USP15, instead of USP15 C269S, deubiquitinates and activates ERK2, followed by translocation of phosphorylated ERK2 from the cytoplasm to the nucleus. Taken together, our study revealed a positive feedback regulation between USP15 and ERK2, which plays a critical role in the interaction of SMAD and non-SMAD signaling pathways to promote cartilage repair in experimental OA. Therefore, this specific mechanism can guide clinical treatments of OA.

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“…If USP15 was knocked out, ERK2 would undergo more ubiquitination modi cations. The most common role in ubiquitination is protein degradation (42)(43)(44) Surprisingly, even though USP15 could deubiquitinate ERK2, the degradation of endogenous ERK2 was not changed by USP15. Next, we identi ed that the total ERK2 levels were unchanged when treated with the proteasome inhibitor MG132.…”

Section: Discussionmentioning

confidence: 99%

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

Wang¹,

Zhu²,

Sun³

et al. 2020

Preprint

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Background.The transforming growth factor-β (TGF-β) signaling pathway plays an essential role in maintaining homeostasis in joints affected by osteoarthritis (OA). Determine the specific relationship between non-SMAD and classical SMAD signaling pathways.Methods.First,we found from human cartilage tissue specimens positive expressions of TGF-β1 and USP15between normal andosteoarthritiscartilage tissueby immunohistochemical.Then, overexpressing and knocking out USP15 or ERK2 followed bythe latest gene editing technology Crispr/Cas9 supported the studyinvitro.And we established rat knee OAmodelsthrough anterior cruciate ligament transection in combination with partial medial meniscectomy (ACLT+pMMx)after 8 weeksand conducted the corresponding Adeno-associated virus (AAV) intraarticular injections. Next, experimental data including immunohistochemical staining,HE/Safranin-O fast green staining,histological evidence analysis,relevant Osteoarthritis Research Society International (OARSI) scoresand expressions of molecules in cartilage anabolismindicated that the relationship betweenERK2 and USP15 throughTGF-β signaling pathway in vivo.Finally, we observed the specific mechanismof USP15 on ERK2 throughco-immunoprecipitation,deubiquitination assay, immunofluorescence and nuclear plasma separation.Results.Here, we detected that ERK2 of non-SMAD signaling can maintain the cartilage phenotype by activating the TGF-β/Smad signaling pathway throughincreasing USP15 in vitro and in vivo. Most importantly, USP15 is required during this process and can form a complex with ERK2 to regulate ubiquitination of ERK2.Specifically,USP15, instead of USP15 C269S, deubiquitinates and activates ERK2, followed by translocation of phosphorylated ERK2 from the cytoplasm to the nucleus. Correspondingly, the level of phosphorylated ERK2 was increased by injecting AAV-mediated overexpressing USP15 into the rat OA model. Conclusion.Taken together, our study revealed a positive feedback regulation between USP15 and ERK2, which plays a critical role in the interaction of SMAD and non-SMAD signaling pathways to promote cartilage repair in experimental OA.

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Host-mediated ubiquitination of a mycobacterial protein suppresses immunity

Cited by 69 publications

References 31 publications

APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

Positive Feedback Regulation between USP15 and ERK2 Promotes Cartilage Repair Through the TGF-β/SMAD2 signaling

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

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Host-mediated ubiquitination of a mycobacterial protein suppresses immunity

Cited by 69 publications

References 31 publications

APC2CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

APC2CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

Positive Feedback Regulation between USP15 and ERK2 Promotes Cartilage Repair Through the TGF-β/SMAD2 signaling

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

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APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7

APC2^CDH1negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7