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The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy Mohamud, Yasir; Xue, Yuan Chao; Liu, Huitao; Ng, Chen Seng; Bahreyni, Amirhossein; Jan, Eric; Luo, Honglin
Abstract
The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected over 50 million individuals’ worldwide with more than ~1 million fatalities. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks urge for better understanding of viral subversion of autophagy. Using MHV-A59 as a model betacoronavirus, time-course infections revealed significant loss in the protein level of ULK1, a canonical autophagy-regulating kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target ULK1, we conducted in-vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from a Cterminal substrate recognition region. Over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagy.
Item Metadata
| Title |
The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy
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| Creator | |
| Contributor | |
| Publisher |
Biochemical and Biophysical Research Communications
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| Date Issued |
2021-02-12
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| Description |
The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected over 50 million individuals’ worldwide with more than ~1 million fatalities. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks urge for better understanding of viral subversion of autophagy. Using MHV-A59 as a model betacoronavirus, time-course infections revealed significant loss in the protein level of ULK1, a canonical autophagy-regulating kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target ULK1, we conducted in-vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from a Cterminal substrate recognition region. Over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagy.
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| Subject | |
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| Language |
eng
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| Date Available |
2022-02-12
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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| DOI |
10.14288/1.0396107
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| URI | |
| Affiliation | |
| Citation |
Mohamud, Y., Xue, Y. C., Liu, H., Ng, C. S., Bahreyni, A., Jan, E., & Luo, H. (2021). The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy. Biochemical and Biophysical Research Communications, 540, 75-82.
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| Publisher DOI |
10.1016/j.bbrc.2020.12.091
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty; Researcher; Graduate
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International