Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis
ABSTRACT Enterovirus infections can cause severe complications, such as poliomyelitis, encephalitis, myocarditis, meningitis, neurological pulmonary edema, and even death. Here, we used genome-wide CRISPR screens to gain new insight into the mechanism by which enteroviruses co-opt host pathways to p...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-02-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02717-21 |
| _version_ | 1819280522323427328 |
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| author | Yu-An Kung Huan-Jung Chiang Mei-Ling Li Yu-Nong Gong Hsin-Ping Chiu Chuan-Tien Hung Peng-Nien Huang Sheng-Yu Huang Pei-Yu Wang Tsu-An Hsu Gary Brewer Shin-Ru Shih |
| author_facet | Yu-An Kung Huan-Jung Chiang Mei-Ling Li Yu-Nong Gong Hsin-Ping Chiu Chuan-Tien Hung Peng-Nien Huang Sheng-Yu Huang Pei-Yu Wang Tsu-An Hsu Gary Brewer Shin-Ru Shih |
| author_sort | Yu-An Kung |
| collection | DOAJ |
| description | ABSTRACT Enterovirus infections can cause severe complications, such as poliomyelitis, encephalitis, myocarditis, meningitis, neurological pulmonary edema, and even death. Here, we used genome-wide CRISPR screens to gain new insight into the mechanism by which enteroviruses co-opt host pathways to potentiate replication and propagation. We found that acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is involved in viral replication organelle formation. ACSL4 is a key component of ferroptosis, an iron-dependent, nonapoptotic programmed cell death. Our results indicated that enteroviruses and coronaviruses can induce ferroptosis via ACSL4. Most importantly, ferroptosis inhibitors, including two FDA-approved drugs, rosiglitazone (ROSI; ACSL4 inhibitor) and pioglitazone (PIO; ACSL4 inhibitor), decreased the viral load of human enteroviruses and coronaviruses, suggesting that ACSL4 is a target for counteracting viral infection. IMPORTANCE We provide the first evidence for the role of ACSL4 in enterovirus replication organelle formation. Moreover, both enteroviruses and coronaviruses induce ferroptosis via ACSL4. These findings establish a novel regulatory mechanism for viral replication. The inhibition of ACSL4 by ferroptosis inhibitors can reduce viral yields of enteroviruses and coronaviruses, including SARS-CoV-2, implying that ACSL4-mediated ferroptosis is a promising therapeutic target for viral diseases. |
| first_indexed | 2024-12-24T00:45:08Z |
| format | Article |
| id | doaj.art-296ab0bacfe54232b59880a5976bf66c |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-24T00:45:08Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-296ab0bacfe54232b59880a5976bf66c2022-12-21T17:23:49ZengAmerican Society for MicrobiologymBio2150-75112022-02-0113110.1128/mbio.02717-21Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via FerroptosisYu-An Kung0Huan-Jung Chiang1Mei-Ling Li2Yu-Nong Gong3Hsin-Ping Chiu4Chuan-Tien Hung5Peng-Nien Huang6Sheng-Yu Huang7Pei-Yu Wang8Tsu-An Hsu9Gary Brewer10Shin-Ru Shih11Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanDepartment of Biochemistry & Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USAResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, TaiwanDepartment of Biochemistry & Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USAResearch Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan City, TaiwanABSTRACT Enterovirus infections can cause severe complications, such as poliomyelitis, encephalitis, myocarditis, meningitis, neurological pulmonary edema, and even death. Here, we used genome-wide CRISPR screens to gain new insight into the mechanism by which enteroviruses co-opt host pathways to potentiate replication and propagation. We found that acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is involved in viral replication organelle formation. ACSL4 is a key component of ferroptosis, an iron-dependent, nonapoptotic programmed cell death. Our results indicated that enteroviruses and coronaviruses can induce ferroptosis via ACSL4. Most importantly, ferroptosis inhibitors, including two FDA-approved drugs, rosiglitazone (ROSI; ACSL4 inhibitor) and pioglitazone (PIO; ACSL4 inhibitor), decreased the viral load of human enteroviruses and coronaviruses, suggesting that ACSL4 is a target for counteracting viral infection. IMPORTANCE We provide the first evidence for the role of ACSL4 in enterovirus replication organelle formation. Moreover, both enteroviruses and coronaviruses induce ferroptosis via ACSL4. These findings establish a novel regulatory mechanism for viral replication. The inhibition of ACSL4 by ferroptosis inhibitors can reduce viral yields of enteroviruses and coronaviruses, including SARS-CoV-2, implying that ACSL4-mediated ferroptosis is a promising therapeutic target for viral diseases.https://journals.asm.org/doi/10.1128/mbio.02717-21genome-wide CRISPR screensACSL4enteroviruscoronavirusferroptosis |
| spellingShingle | Yu-An Kung Huan-Jung Chiang Mei-Ling Li Yu-Nong Gong Hsin-Ping Chiu Chuan-Tien Hung Peng-Nien Huang Sheng-Yu Huang Pei-Yu Wang Tsu-An Hsu Gary Brewer Shin-Ru Shih Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis mBio genome-wide CRISPR screens ACSL4 enterovirus coronavirus ferroptosis |
| title | Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis |
| title_full | Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis |
| title_fullStr | Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis |
| title_full_unstemmed | Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis |
| title_short | Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis |
| title_sort | acyl coenzyme a synthetase long chain family member 4 is involved in viral replication organelle formation and facilitates virus replication via ferroptosis |
| topic | genome-wide CRISPR screens ACSL4 enterovirus coronavirus ferroptosis |
| url | https://journals.asm.org/doi/10.1128/mbio.02717-21 |
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