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The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Here we present a pivotal molecular mechanism of viral protein translation that relies on the mitochondrial translation machinery. We found that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for the regulation of viral protein expression. SARS-CoV-2 controls the translation of its spike gene by hijacking host mitochondria through 5 leader and 3UTR sequences that contain mitochondrial localization signals and activate the EGR1 pathway. Mitochondrial-targeted drugs such as lonidamine and polydatin significantly repress rare codon-driven gene expression and viral replication. This study identifies an unreported viral protein translation mechanism and opens up a novel avenue for developing antiviral drugs. One Sentence SummaryMitochondria are a potential target for antiviral therapy
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ObjectiveTo evaluate the expression of endothelial differentiation gene/lysophosphatidic acid (LPA) receptors (Edg/LPA) and its clinical significance in human pancreatic cancer.MethodsFifty cases of pancreatic cancer and adjacent normal tissues were collected,and Real-time PCR,Western blot and immunohistochemistry was used to determine the expression of Edg-2/LPA1,Edg-4/LPA2 and Edg-7/LPA3 receptors mRNA and protein,and its relationship with clinicopathological parameters was analyzed.Results The expressions of Edg-2/LPA1,Edg-4/LPA2,Edg-7/LPA3 receptor mRNA were (0.142 ± 0.042 ) ％,(0.471 ±0.064)％,(0.231 ±0.043)％ in pancreatic cancer,and the corresponding values were (0.132 ±0.029)％,(0.027 ±0.015)％,(0.163 ±0.046)％ in adjacent normal tissues.The expressions of Edg-4/LPA2 receptor mRNA in pancreatic cancer were significantly lower than that in adjacent normal tissues ( P ＜0.05 ).The expressions of Edg-4/LPA2 receptor protein in pancreatic cancer were significantly lower than that in adjacent normal tissues ( P ＜ 0.05 ).The expressions of three types of Edg /LPA receptor mRNA in pancreatic cancer were parallel to serum CA19-9 levels.The expressions of Edg-4/LPA2 receptor mRNA were associated with tumor size,differentiation degree,and invasive ability and metastasis.While the expressions of Edg-2/LPA1,Edg-7/LPA3 receptor mRNA was associated with invasive ability and metastasis only.ConclusionsEdg-4/LPA2 receptor is highly expressed in pancreatic cancer,which suggesting the malignant biological behavior of pancreatic cancer.
