Ubiquitin E3 ligase MID1 inhibits the innate immune response by ubiquitinating IRF3

Chen, Xiangjie; Xu, Ying; Tu, Wenzhi; Huang, Fan; Zuo, Yibo; Zhang, Hongguang; Jin, Lincong; Ren, Tengfei; He, Jiuyi; Miao, Ying; Yuan, Yukang; Zhao, Qian; Liu, Jiapeng; Zhang, Renxia; Zhu, Li; Feng, Qian; Zhu, Chengliang; Zheng, Hui; Wang, Jun

doi:10.1111/imm.13315

Cited by 18 publications

(13 citation statements)

References 26 publications

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“…It is also noteworthy that Spike (nor 3C-like protease) is not known to confer E3 ubiquitin ligase function. As multiple E3 ligases have been described in fostering the degradation of IRF3, further investigation will be required to determine which E3(s) and potential co-factors cooperate with Spike to degrade IRF3 ( Higgs et al., 2008 ; Zhang et al., 2008 ; Yu and Hayward, 2010 ; Lei et al., 2013 ; Wang et al., 2015 , Chen et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Freitas

Crum

Parvatiyar

2022

Front. Cell. Infect. Microbiol.

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Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Freitas

Crum

Parvatiyar

2022

Front. Cell. Infect. Microbiol.

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“…Usually, seven lysine residues and an N‐terminus of ubiquitin are served for protein ubiquitination, including K6, K11, K27, K29, K33, K48, K63 and M1 24 . The role of K48 and K63 is well studied for facilitating or preventing proteasomal degradation of the substrate protein, respectively 34–38 . K11‐linked chains are often accompanied by the K48 counterparts in regulating protein degradation involved in cell mitosis, 39 as well as protein expressions of type 1 interferon 40 and hypoxia‐inducible factors HIF1α and HIF2α 41 .…”

Section: Discussionmentioning

confidence: 99%

Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer

Jiang

Chen

et al. 2022

Clinical & Translational Med

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Background Cyclin C (CCNC) was reported to take part in regulating mitochondria‐derived oxidative stress under cisplatin stimulation. However, its effect in gastric cancer is unknown. This study aimed to investigate the role of cyclin C and its ubiquitylation in regulating cisplatin resistance in gastric cancer. Methods The interaction between HECT domain and ankyrin repeat‐containing E3 ubiquitin‐protein ligase 1 (HACE1) and cyclin C was investigated by GST pull‐down assay, co‐immunoprecipitation and ubiquitylation assay. Mitochondria‐derived oxidative stress was studied by MitoSOX Red assay, seahorse assay and mitochondrial membrane potential measurement. Cyclin C‐associated cisplatin resistance was studied in vivo via xenograft. Results HACE1 catalysed the ubiquitylation of cyclin C by adding Lys11‐linked ubiquitin chains when cyclin C translocates to cytoplasm induced by cisplatin treatment. The ubiquitin‐modified cyclin C then anchor at mitochondira, which induced mitochondrial fission and ROS synthesis. Depleting CCNC or mutation on the ubiquitylation sites decreased mitochondrial ROS production and reduced cell apoptosis under cisplatin treatment. Xenograft study showed that disrupting cyclin C ubiquitylation by HACE1 conferred impairing cell apoptosis response upon cisplatin administration. Conclusions Cyclin C is a newly identified substrate of HACE1 E3 ligase. HACE1‐mediated ubiquitylation of cyclin C sheds light on a better understanding of cisplatin‐associated resistance in gastric cancer patients. Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer. With cisplatin‐induced nuclear–mitochondrial translocation of cyclin C, its ubiquitylation by HACE1 increased mitochondrial fission and mitochondrial‐derived oxidative stress, leading to cell apoptosis.

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“…The family of TRIM-containing protein is a subfamily of E3 that regulates diabetes mellitus complications such as TRIM13 and TRIM16 ( Li et al, 2017 , 2020 ). TRIM18 is a member of the TRIM superfamily that is involved in multiple cellular processes, such as proliferation, apoptosis, fibrosis, and inflammation, as a result of the diversity of its substrates ( Zhang et al, 2018 ; Collison et al, 2019 ; Zanchetta and Meroni, 2019 ; Chen et al, 2021 ). Moreover, on transcriptome analysis, TRIM18 expression was found to be increased in renal tubules rather than in renal glomeruli in patients with DKD ( Woroniecka et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

TRIM18-Regulated STAT3 Signaling Pathway via PTP1B Promotes Renal Epithelial–Mesenchymal Transition, Inflammation, and Fibrosis in Diabetic Kidney Disease

et al. 2021

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Diabetic kidney disease (DKD) has become a key cause of end-stage renal disease worldwide. Inflammation and fibrosis have been shown to play important roles in the pathogenesis of DKD. MID1, also known as TRIM18, is an E3 ubiquitin ligase of the tripartite motif (TRIM) subfamily of RING-containing proteins and increased in renal tubule in patients with DKD. However, the function and molecular mechanism of TRIM18 in DKD remain unexplored. Herein we report that TRIM18 expression levels were increased in patients with DKD. An animal study confirms that TRIM18 is involved in kidney injury and fibrosis in diabetic mice. TRIM18 knockdown inhibits high glucose (HG)-induced epithelial–mesenchymal transition (EMT), inflammation, and fibrosis of HK-2 cells. This is accompanied by decreased levels of tumor necrosis factor alpha, interleukin-6, hydroxyproline (Hyp), connective tissue growth factor, and α-smooth muscle actin. Additionally, TRIM18 knockdown inhibits HG-induced increase in the phosphorylated-/total signal transducer and activator of transcription (STAT3). Treatment with niclosamide (STAT3 inhibitor) or protein tyrosine phosphatase-1B (PTP1B) overexpression blocked the TRIM18 induced EMT, inflammation and fibrosis. Co-immunoprecipitation and Western blot assays showed that TRIM18 promoted the ubiquitination of PTP1B. These findings highlight the importance of the TRIM18/PTP1B/STAT3 signaling pathway in DKD and can help in the development of new therapeutics for DKD treatment.

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Ubiquitin E3 ligase MID1 inhibits the innate immune response by ubiquitinating IRF3

Cited by 18 publications

References 26 publications

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer

TRIM18-Regulated STAT3 Signaling Pathway via PTP1B Promotes Renal Epithelial–Mesenchymal Transition, Inflammation, and Fibrosis in Diabetic Kidney Disease

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