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Article ; Online: SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1

Sin-Yee Fung / Kam-Leung Siu / Huayue Lin / Ching-Ping Chan / Man Lung Yeung / Dong-Yan Jin

Cell & Bioscience, Vol 12, Iss 1, Pp 1-

2022 Volume 12

Abstract: Abstract Background SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might ... ...

Abstract	Abstract Background SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling. Results In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1. Conclusion SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1.
Keywords	SARS-CoV-2 ; COVID-19 ; NSP13 ; Helicase ; JAK1 ; STAT1 ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	570
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3.

Fung, Sin-Yee / Siu, Kam-Leung / Lin, Huayue / Yeung, Man Lung / Jin, Dong-Yan

International journal of biological sciences

2021 Volume 17, Issue 6, Page(s) 1547–1554

Abstract: Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. ...

Abstract	Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. In this study, we reported on the IFN antagonism of SARS-CoV-2 main protease NSP5. NSP5 proteins of both SARS-CoV and SARS-CoV-2 counteracted Sendai virus-induced IFN production. NSP5 variants G15S and K90R commonly seen in circulating strains of SARS-CoV-2 retained the IFN-antagonizing property. The suppressive effect of NSP5 on IFN-β gene transcription induced by RIG-I, MAVS, TBK1 and IKKϵ suggested that NSP5 likely acts at a step downstream of IRF3 phosphorylation in the cytoplasm. NSP5 did not influence steady-state expression or phosphorylation of IRF3, suggesting that IRF3, regardless of its phosphorylation state, might not be the substrate of NSP5 protease. However, nuclear translocation of phosphorylated IRF3 was severely compromised in NSP5-expressing cells. Taken together, our work revealed a new mechanism by which NSP5 proteins encoded by SARS-CoV and SARS-CoV-2 antagonize IFN production by retaining phosphorylated IRF3 in the cytoplasm. Our findings have implications in rational design and development of antiviral agents against SARS-CoV-2.
MeSH term(s)	Animals ; COVID-19/virology ; Cell Nucleus/metabolism ; Chlorocebus aethiops ; Coronavirus 3C Proteases/metabolism ; Humans ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/biosynthesis ; Phosphorylation ; Protein Transport ; SARS-CoV-2/enzymology ; Vero Cells
Chemical Substances	IRF3 protein, human ; Interferon Regulatory Factor-3 ; Interferon Type I ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2021-04-10
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2179208-2
ISSN	1449-2288 ; 1449-2288
ISSN (online)	1449-2288
ISSN	1449-2288
DOI	10.7150/ijbs.59943
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1.

Fung, Sin-Yee / Siu, Kam-Leung / Lin, Huayue / Chan, Ching-Ping / Yeung, Man Lung / Jin, Dong-Yan

Cell & bioscience

2022 Volume 12, Issue 1, Page(s) 36

Abstract: Background: SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result ... ...

Abstract	Background: SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling. Results: In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1. Conclusion: SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1.
Language	English
Publishing date	2022-03-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-022-00770-1
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Article: SARS-CoV-2 and COVID-19: The most important research questions.

Yuen, Kit-San / Ye, Zi-Wei / Fung, Sin-Yee / Chan, Chi-Ping / Jin, Dong-Yan

Cell & bioscience

2020 Volume 10, Page(s) 40

Abstract: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, asymptomatic and ... ...

Abstract	Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis.
Keywords	covid19
Language	English
Publishing date	2020-03-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-020-00404-4
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Article ; Online: Superoxide dismutase A (SodA) is a c-di-GMP effector protein governing oxidative stress tolerance in Stenotrophomonas maltophilia.

Sun, Xiao-Yu / Deng, Jie / Zhang, Chenhui / Fung, Sin-Yee / Siu, Kam-Leung / Cheng, Ying-Ying / Ye, Liumei / Qin, Jiaoxia / Wang, Ke / Qu, Jiu-Xin / Gao, Wenying / Wang, Fuxiang / Jin, Dong-Yan / Yang, Liang

Microbiological research

2023 Volume 278, Page(s) 127535

Abstract: C-di-GMP is a bacterial second messenger implicated in the regulation of many key functions including antibiotic tolerance and biofilm formation. Our understanding of how c-di-GMP exerts its action via receptors to modulate different biological functions ...

Abstract	C-di-GMP is a bacterial second messenger implicated in the regulation of many key functions including antibiotic tolerance and biofilm formation. Our understanding of how c-di-GMP exerts its action via receptors to modulate different biological functions is still limited. Here we used a c-di-GMP affinity pull-down assay coupled to LC-MS/MS to identify c-di-GMP-binding proteins in the opportunistic pathogen Stenotrophomonas maltophilia. This analysis identified Smlt3238 (SodA), a protein of the superoxide dismutase family, as a c-di-GMP-binding protein. Microscale thermophoresis showed that purified SodA protein bound c-di-GMP with an estimated dissociation constant (Kd) value of 141.5 μM. Using various in vivo and in vitro experiments, we demonstrated that c-di-GMP modulates the enzyme activity of SodA directly. Circular dichroism experiments revealed that SodA protein gradually altered its basic structure with increasing levels of c-di-GMP. Phenotypic experiments conducted in the presence of a range of intracellular c-di-GMP levels showed that SodA function is modulated by c-di-GMP. The findings thus identify a novel c-di-GMP binding protein that governs oxidative stress tolerance in S. maltophilia.
MeSH term(s)	Stenotrophomonas maltophilia/metabolism ; Bacterial Proteins/metabolism ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Cyclic GMP/metabolism ; Superoxide Dismutase/metabolism ; Carrier Proteins/metabolism ; Oxidative Stress ; Gene Expression Regulation, Bacterial ; Biofilms
Chemical Substances	bis(3',5')-cyclic diguanylic acid (61093-23-0) ; Bacterial Proteins ; Cyclic GMP (H2D2X058MU) ; Superoxide Dismutase (EC 1.15.1.1) ; Carrier Proteins
Language	English
Publishing date	2023-10-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1189614-0
ISSN	1618-0623 ; 0944-5013
ISSN (online)	1618-0623
ISSN	0944-5013
DOI	10.1016/j.micres.2023.127535
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Article ; Online: SARS-CoV-2 and COVID-19

Kit-San Yuen / Zi-Wei Ye / Sin-Yee Fung / Pak-Hin Hinson Cheung / Chi-Ping Chan / Dong-Yan Jin

Cell & Bioscience, Vol 11, Iss 1, Pp 1-

revisiting the most important research questions

2021 Volume 6

Abstract: Abstract In February 2020, we highlighted the top nine important research questions on SARS-CoV-2 and COVID-19 concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and ... ...

Abstract	Abstract In February 2020, we highlighted the top nine important research questions on SARS-CoV-2 and COVID-19 concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis. These and related questions are revisited at the end of 2021 to shed light on the roadmap of bringing an end to the pandemic.
Keywords	SARS-CoV-2 ; COVID-19 ; Pandemic ; Endemic ; Vaccines ; Antivirals ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: SARS-CoV-2 and COVID-19: revisiting the most important research questions.

Yuen, Kit-San / Ye, Zi-Wei / Fung, Sin-Yee / Cheung, Pak-Hin Hinson / Chan, Chi-Ping / Jin, Dong-Yan

Cell & bioscience

2021 Volume 11, Issue 1, Page(s) 215

Abstract: In February 2020, we highlighted the top nine important research questions on SARS-CoV-2 and COVID-19 concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral ... ...

Abstract	In February 2020, we highlighted the top nine important research questions on SARS-CoV-2 and COVID-19 concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis. These and related questions are revisited at the end of 2021 to shed light on the roadmap of bringing an end to the pandemic.
Language	English
Publishing date	2021-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-021-00730-1
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Article ; Online: A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses.

Fung, Sin-Yee / Yuen, Kit-San / Ye, Zi-Wei / Chan, Chi-Ping / Jin, Dong-Yan

Emerging microbes & infections

2020 Volume 9, Issue 1, Page(s) 558–570

Abstract: World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International ... ...

Abstract	World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.
MeSH term(s)	Animals ; Betacoronavirus/isolation & purification ; Betacoronavirus/physiology ; COVID-19 ; Coronavirus Infections/epidemiology ; Coronavirus Infections/prevention & control ; Coronavirus Infections/transmission ; Coronavirus Infections/virology ; Disease Vectors ; Host-Pathogen Interactions ; Humans ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/prevention & control ; Pneumonia, Viral/transmission ; Pneumonia, Viral/virology ; SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-03-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2681359-2
ISSN	2222-1751 ; 2222-1751
ISSN (online)	2222-1751
ISSN	2222-1751
DOI	10.1080/22221751.2020.1736644
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Article ; Online: Identification of Lysine Acetylation Sites on MERS-CoV Replicase pp1ab.

Zhu, Lin / Fung, Sin-Yee / Xie, Guangshan / Wong, Lok-Yin Roy / Jin, Dong-Yan / Cai, Zongwei

Molecular & cellular proteomics : MCP

2020 Volume 19, Issue 8, Page(s) 1303–1309

Abstract: MERS is a life-threatening disease and MERS-CoV has the potential to cause the next pandemic. Protein acetylation is known to play a crucial role in host response to viral infection. Acetylation of viral proteins encoded by other RNA viruses have been ... ...

Abstract	MERS is a life-threatening disease and MERS-CoV has the potential to cause the next pandemic. Protein acetylation is known to play a crucial role in host response to viral infection. Acetylation of viral proteins encoded by other RNA viruses have been reported to affect viral replication. It is therefore of interest to see whether MERS-CoV proteins are also acetylated. Viral proteins obtained from infected cells were trypsin-digested into peptides. Acetylated peptides were enriched by immunoprecipitation and subject to nano-LC-Orbitrap analysis. Bioinformatic analysis was performed to assess the conservation level of identified acetylation sites and to predict the upstream regulatory factors. A total of 12 acetylation sites were identified from 7 peptides, which all belong to the replicase polyprotein pp1ab. All identified acetylation sites were found to be highly conserved across MERS-CoV sequences in NCBI database. Upstream factors, including deacetylases of the SIRT1 and HDAC families as well as acetyltransferases of the TIP60 family, were predicted to be responsible for regulating the acetylation events identified. Western blotting confirms that acetylation events indeed occur on pp1ab protein by expressing NSP4 in HEK293 cells. Acetylation events on MERS-CoV viral protein pp1ab were identified for the first time, which indicate that MERS-CoV might use the host acetylation machinery to regulate its enzyme activity and to achieve optimal replication. Upstream factors were predicted, which might facilitate further analysis of the regulatory mechanism of MERS-CoV replication.
MeSH term(s)	Acetylation ; HEK293 Cells ; Humans ; Lysine/metabolism ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Viral Proteins/metabolism
Chemical Substances	Viral Proteins ; Lysine (K3Z4F929H6)
Keywords	covid19
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.RA119.001897
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Article ; Online: SARS-CoV-2 and COVID-19

Kit-San Yuen / Zi -Wei Ye / Sin-Yee Fung / Chi-Ping Chan / Dong-Yan Jin

Cell & Bioscience, Vol 10, Iss 1, Pp 1-

The most important research questions

2020 Volume 5

Abstract: Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, ... ...

Abstract	Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis.
Keywords	SARS-CoV-2 ; COVID-19 ; 2019 novel coronavirus (2019-nCoV) ; Novel coronavirus pneumonia (NCP) ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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