Aflatoxin B_1(AFB_1) is one of the most potent mycotoxins affecting human health and animal production.To deeply understand the hosttoxin interaction,we performed CRISPR screening and identified cystathionine β-synth...Aflatoxin B_1(AFB_1) is one of the most potent mycotoxins affecting human health and animal production.To deeply understand the hosttoxin interaction,we performed CRISPR screening and identified cystathionine β-synthase(CBS) as a critical host gene affecting AFB_1 cytotoxicity.Mechanistic studies revealed that CBS affects AFB_1-induced cell death by regulating the abundance of protein post-translational modifications(PTMs) in host cells.First,AFB_1 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 intramitochondrial SAM levels by rescuing the perturbed methionine cycle after AFB_1 exposure,thereby alleviating AFB_1-induced cell death.Second,AFB_1 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_1-induced cell death.We also investigated two PTM-regulating small molecules,SAM and PR-619,which can increase cell viability in AFB_1-exposed cells.展开更多
基金supported by the National Natural Science Foundation of China (32372874)the Biological Breeding-National Science and Technology Major Project (2023ZD0404303)。
文摘Aflatoxin B_1(AFB_1) is one of the most potent mycotoxins affecting human health and animal production.To deeply understand the hosttoxin interaction,we performed CRISPR screening and identified cystathionine β-synthase(CBS) as a critical host gene affecting AFB_1 cytotoxicity.Mechanistic studies revealed that CBS affects AFB_1-induced cell death by regulating the abundance of protein post-translational modifications(PTMs) in host cells.First,AFB_1 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 intramitochondrial SAM levels by rescuing the perturbed methionine cycle after AFB_1 exposure,thereby alleviating AFB_1-induced cell death.Second,AFB_1 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_1-induced cell death.We also investigated two PTM-regulating small molecules,SAM and PR-619,which can increase cell viability in AFB_1-exposed cells.
