Modeling neurodevelopmental disorder- associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1

• 成果类型: Article
• 署名作者: Duan, Ye; Li, Li; Panzade, Ganesh Prabhakar; Piton, Amelie; Zinovyeva, Anna; Ambros, Victor
• 署名单位: University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Harvard University; Kansas State University; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11892
• DOI: 10.1073/pnas.2308255121
• 发表日期: 2024-03-05
• 关键词: messenger-rna decay; c-elegans; proteins; proteostasis; translation; expression; PATHWAY; domain; genes

摘要

MicroRNAs (miRNA) associate with Argonaute (AGO) proteins and repress gene expression by base pairing to sequences in the 3 ' untranslated regions of target genes. De novo coding variants in the human AGO genes AGO1 and AGO2 cause neurodevelopmental disorders (NDD) with intellectual disability, referred to as Argonaute syndromes. Most of the altered amino acids are conserved between the miRNA- associated AGO in Homo sapiens and Caenorhabditis elegans, suggesting that the human mutations could disrupt conserved functions in miRNA biogenesis or activity. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homologous gene, alg-1. These alg-1 NDD mutations cause phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC (miRNA silencing complex) formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic, causing developmental and molecular phenotypes stronger than those of alg-1 null mutants, likely by sequestrating functional miRISC components into non- functional complexes. The alg-1 NDD mutations cause allele- specific disruptions in mature miRNA profiles, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or messenger RNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental AGO functions and provide insights into the conservation of miRNA- mediated post- transcriptional regulatory mechanisms.