Mortalin: A new regulator for siRNA-guided post-transcriptional gene silencing in neural cells

Arezou Arvand
MSc Student 
Department of Biochemistry

Date: November 18, 2024
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

Abstract:

RNA interference (RNAi) is a fundamental mechanism of post-transcriptional gene regulation mediated by small non-coding RNAs, such as small interfering RNAs (siRNAs), through the RNA-induced silencing complex (RISC), of which Argonaute 2 (AGO2) is the essential component. While the core components of the RNAi pathway, namely AGO2, are well characterized, the role of its interacting partners, especially cellular chaperones remain poorly understood. Among these chaperones, glucose-regulated protein 75 (GRP75), a member of the heat-shock protein 70 (HSP70) family, has gained attention for its multifaceted involvement in cellular processes, particularly within the context of small non-coding RNAs, such as siRNAs. Notably, HSPs have been shown to help load siRNA duplexes into AGO proteins within the RISC, which is crucial for the decay of target transcripts, thereby rendering specific gene silencing. The current study investigates the function of Mortalin in siRNA-mediated gene silencing in neuroblastoma. Through mitochondrial fractionation, in vitro manipulation of gene expression in cell culture models, and co-immunoprecipitation experiments, we demonstrated that loss of Mortalin significantly downregulates the expression of AGO2 while increasing the protein levels of Dicer, a key component in the RNAi pathway, besides AGO2. We identified a novel interaction between Mortalin and AGO2 that occurs in both the cytosolic and mitochondrial compartments, suggesting a potential new regulatory mechanism governed by Mortalin in the mitochondrial RNAi pathway, thus providing new avenues for developing strategies that enhance siRNA-based therapeutic outcomes in treating neurological disorders.