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<p>Aflatoxin B<sub>1</sub> (AFB<sub>1</sub>) is one of the most potent mycotoxins affecting human health and animal production. To deeply understand the host-toxin interaction, we performed CRISPR screening and identified cystathionine β-synthase (CBS) as a critical host gene affecting AFB<sub>1</sub> cytotoxicity. Mechanistic studies revealed that CBS affects AFB<sub>1</sub>-induced cell death by regulating the abundance of protein post-translational modifications (PTMs) in host cells. First, AFB<sub>1</sub> disrupted the transfer of S-adenosylmethionine (SAM) from the cytoplasm to the mitochondria, thereby reducing the intra-mitochondrial protein methylation level. Deficient intra-mitochondrial protein methylation impaired mitochondrial function and caused cell death. CBS knockout (KO) can enhance SAM generation and mobilization to restore intra-mitochondrial SAM levels by rescuing the perturbed methionine cycle after AFB<sub>1</sub> exposure, thereby alleviating AFB<sub>1</sub>-induced cell death. Second, AFB<sub>1</sub> decreased global protein ubiquitination levels by affecting gene expression of ubiquitin-modified enzymes. CBS-KO and pharmaceutical treatment correcting gene expression of ubiquitin-modified enzymes can rescue AFB<sub>1</sub>-induced cell death. We also investigated two PTM-regulating small molecules, SAM and PR-619, which can increase cell viability in AFB<sub>1</sub>-exposed cells.</p>

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CRISPR screening identifies protein methylation and ubiquitination modifications that modulate aflatoxin B1 cytotoxicity

  • 期刊论文

  • 发表日期：

    2025年3月27日

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  • Huaqiang Yang,
  • Xi Ji,
  • Haiwen Zhong,
  • Xiaohui Yang,
  • Dandan Hu,
  • Gengyuan Cai,
  • Zhenfang Wu

摘要

Aflatoxin B1 (AFB1) is one of the most potent mycotoxins affecting human health and animal production. To deeply understand the host-toxin interaction, we performed CRISPR screening and identified cystathionine β-synthase (CBS) as a critical host gene affecting AFB1 cytotoxicity. Mechanistic studies revealed that CBS affects AFB1-induced cell death by regulating the abundance of protein post-translational modifications (PTMs) in host cells. First, AFB1 disrupted the transfer of S-adenosylmethionine (SAM) from the cytoplasm to the mitochondria, thereby reducing the intra-mitochondrial protein methylation level. Deficient intra-mitochondrial protein methylation impaired mitochondrial function and caused cell death. CBS knockout (KO) can enhance SAM generation and mobilization to restore intra-mitochondrial SAM levels by rescuing the perturbed methionine cycle after AFB1 exposure, thereby alleviating AFB1-induced cell death. Second, AFB1 decreased global protein ubiquitination levels by affecting gene expression of ubiquitin-modified enzymes. CBS-KO and pharmaceutical treatment correcting gene expression of ubiquitin-modified enzymes can rescue AFB1-induced cell death. We also investigated two PTM-regulating small molecules, SAM and PR-619, which can increase cell viability in AFB1-exposed cells.