Translation of key viral replicative proteins in coronaviruses requires a programmed –1 ribosomal frameshifting (–1 PRF) event controlled by the viral frameshift-stimulatory element (FSE). Although previous studies have analyzed host factor dependencies of coronaviruses, how host cellular factors alter –1 PRF efficiency and affect viral replication remains poorly understood. Here, using RNA pull-down combined with LC-MS/MS analysis, we identified heterogeneous nuclear ribonucleoprotein C (hnRNPC) as a major interacting protein of FSE RNA. Coronavirus infection triggers hnRNPC mRNA decay, alters hnRNPC protein levels, and induces its cytoplasmic relocalization, where it appears to bind directly to FSE RNA through residues Asn7 and Asn83. This binding is associated with increased –1 PRF efficiency and may facilitate coronavirus replication. Deletion mapping analysis shows that hnRNPC preferentially binds U-rich regions of the FSE RNA. Finally, we demonstrated that the small molecule Elbasvir directly binds hnRNPC, disrupting the interaction between hnRNPC and FSE RNA and inhibiting coronavirus replication by decreasing –1 PRF efficiency. Collectively, our study identifies hnRNPC as a key host cofactor for coronaviruses and provides a novel target for broad-spectrum antiviral drug development.
Jingchen Xu, Hongying Li, Jianrui Li et al.· PLoS Pathogens· 0 citations
Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.
Xinyue Liu, Hu Li, Xuekai Wang et al.· Chinese Journal of Natural M...· 0 citations