Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Article numbere02717
JournalmBio
Volume13
Issue number1
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

Keywords

  • ACSL4
  • Coronavirus
  • Enterovirus
  • Ferroptosis
  • Genome-wide CRISPR screens

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