An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress miRNAs in a longevity model and an alg-1 overexpression model.
Cellular response to redox imbalance is crucial for organismal health. microRNAs are implicated in stress responses. ALG-1, the C. elegans ortholog of human AGO2, plays an essential role in microRNA processing and function. Here we investigated the mechanisms governing ALG-1 expression in C. elegans and the players controlling lifespan and stress resistance downstream of ALG-1. We found that upregulated ALG-1 is a shared feature in conditions linked to increased longevity (e.g., germline-deficient glp-1 mutants). ALG-1 knockdown reduces lifespan and oxidative stress resistance, while overexpression enhances survival against pro-oxidant agents but not heat or reductive stress. R02D3.7 represses alg-1 expression, impacting oxidative stress resistance at least in part via ALG-1. microRNAs upregulated in glp-1 mutants (miR-87-3p, miR-230-3p, and miR-235-3p) can target genes in the protein disulfide isomerase pathway and protect against oxidative stress. This study unveils a tightly regulated network involving transcription factors and microRNAs which controls organisms' ability to withstand oxidative stress. Overall design: To investigate the role of specific miRNAs in oxidative stress resistance in long-lived worms, we examined the miRNA expression profiles in C. elegans strains with either alg-1 overexpression (ALG-1 O/E) or the glp-1(e2144) mutation. We conducted gene expression profiling analysis using data obtained from small RNA-seq, which was enriched for miRNAs, from four different strains. The comparative gene expression profiling analysis included the wild type (WT) strain and the germline-less longevity (glp-1 mutant) strain, as well as animals with alg-1 overexpression (ALG-1 O/E) and its control (CT20) strain.