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| 1 | SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation显示文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is the ongoing global pandemic that poses substantial challenges to public health worldwide.A subset of COVID-19 patients experience systemic inflammatory response,known as cytokine storm,which may lead to death.Receptor-interacting serine/threonine-protein kinase 1(RIPK1)is an important mediator of inflammation and cell death.Here,we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection.We found evidence of RIPK1 activation in human COVID-19 lung pathological samples,and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2.Inhibition of RIPK1 using multiple smallmolecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids.Furthermore,therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load,and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice.Mechanistically,we found that the RNA-dependent RNA polymerase of SARS-CoV-2,NSP12,a highly conserved central component of coronaviral replication and transcription machinery,promoted the activation of RIPK1.Furthermore,NSP12323L variant,encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy,Italy,that carries a Pro323Leu amino acid substitution in NSP12,showed increased ability to activate RIPK1.Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells.Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19. | Gang Xu Ying Li Shengyuan Zhang Haoran Peng Yunyun Wang Dekang Li Taijie Jin Zhuohao He Yilun Tong Chunting Qi Guowei Wu Kangyun Dong Jizhou Gou Yang Liu Tongyang Xiao Jing Qu Liang Li Liang Liu Ping Zhao Zheng Zhang Junying Yuan | 2021 | Cell Research2021，31，12： | 6 |
| 2 | Model- ling and simulation of new product diffusion with nega- tive appraise based on system dynamics: A comparative perspective显示文摘 | Yu Tongyang Gong Xiaoguang Xiao Renbin | 2010 | International Journal of Computer Ap- plications in Technology2010，37，34： | 1 |
| 3 | Multiomics approach reveals the ubiquitination-specific processes hijacked by SARS-CoV-2显示文摘The Coronavirus Disease 2019(COVID-19)caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a global pandemic that seriously threatens health and socioeconomic development,but the existed antiviral drugs and vaccines still cannot yet halt the spread of the epidemic.Therefore,a comprehensive and profound understanding of the pathogenesis of SARS-CoV-2 is urgently needed to explore effective therapeutic targets.Here,we conducted a multiomics study of SARS-CoV-2-infected lung epithelial cells,including transcriptomic,proteomic,and ubiquitinomic.Multiomics analysis showed that SARS-CoV-2-infected lung epithelial cells activated strong innate immune response,including interferon and inflammatory responses.Ubiquitinomic further reveals the underlying mechanism of SARS-CoV-2 disrupting the host innate immune response.In addition,SARS-CoV-2 proteins were found to be ubiquitinated during infection despite the fact that SARS-CoV-2 itself didn’t code any E3 ligase,and that ubiquitination at three sites on the Spike protein could significantly enhance viral infection.Further screening of the E3 ubiquitin ligases and deubiquitinating enzymes(DUBs)library revealed four E3 ligases influencing SARS-CoV-2 infection,thus providing several new antiviral targets.This multiomics combined with high-throughput screening study reveals that SARS-CoV-2 not only modulates innate immunity,but also promotes viral infection,by hijacking ubiquitination-specific processes,highlighting potential antiviral and anti-inflammation targets. | Gang Xu Yezi Wu Tongyang Xiao Furong Qi Lujie Fan Shengyuan Zhang Jian Zhou Yanhua He Xiang Gao Hongxiang Zeng Yunfei Li Zheng Zhang | 2022 | Signal Transduction and Targeted Therapy2022，7，10： | 1 |
| 4 | SARS-CoV-2 helicase NSP13 hijacks the host protein EWSR1 to promote viral replication by enhancing RNA unwinding activity显示文摘Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 and has led to a global coronavirus disease 2019(COVID-19)pandemic.Currently,incomplete understanding of how SARS-CoV-2 arrogates the host cell to establish its life cycle has led to slow progress in the development of effective drugs.Results:In this study,we found that SARS-CoV-2 hijacks the host protein EWSR1(Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1)to promote the activity of its helicase NSP13 to facilitate viral propagation.NSP13 is highly conserved among coronaviruses and is crucial for virus replication,providing chemical energy to unwind viral RNA replication intermediates.Treatment with different SARS-CoV-2 NSP13 inhibitors in multi-ple cell lines infected with SARS-CoV-2 effectively suppressed SARS-CoV-2 infection.Using affinity-purification mass spectrometry,the RNA binding protein EWSR1 was then identified as a potent host factor that physically associated with NSP13.Furthermore,silencing EWSR1 dramatically reduced virus replication at both viral RNA and protein levels.Mechanistically,EWSR1 was found to bind to the NTPase domain of NSP13 and potentially enhance its dsRNA unwinding ability.Conclusions:Our results pinpoint EWSR1 as a novel host factor for NSP13 that could potentially be used for drug repurposing as a therapeutic target for COVID-19. | Hongxiang Zeng Xiang Gao Gang Xu Shengyuan Zhang Lin Cheng Tongyang Xiao Wenhong Zu Zheng Zhang | 2022 | Infectious Medicine2022，1，1： | 0 |
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