Mikro RNAların endoplazmik retikulumdaki katlanmamış protein tepkisi (KPTER)'ndeki rollerini anlamak için pash-1ts suşunun fenotipik analizi

MiRNAs in ̴22 nucleotide long, noncoding RNAs that are post transcriptional gene regulators. Recent studies using conditional temperature‐sensitive (ts) mutant of the miRNA pathway, pash‐1(ts), have established that post‐developmental expression of miRNA is essential for normal lifespan and physiology. Due to the tight link between reduced lifespan and protein quality control, these observations suggest a potential involvement of miRNAs in the regulation of protein homeostasis (proteostasis). During their lifetime, cells are faced with the variety of stresses which are the reason of protein misfolding and aggregation. Throughout evolution, organisms improve stress response mechanisms to deal with the disruption of protein homeostasis. One of the stress response mechanisms is endoplasmic reticulum unfolded protein response (UPRER). UPRER is crucial not just as a stress response mechanism but also as a regulator of amino acid metabolism, the energy homeostasis and also it is indispensable for the embryonic development. The overall aim of my thesis is to investigate and establish the mechanisms by which miRNAs are involved in the regulation of UPRER upon activation of the stress response mechanisms. This has been examined by testing the effects of pash-1(ts) mutant on expression and regulation of stress genes involved in the cellular protein quality control and testing the ability of pash‐1(ts) mutants to respond to ER stress challenges that induce the UPRER. Our results demonstrated that compromised miRNA production leads to the activation of HSP-4, C. elegans homolog of BiP, in various tissues. Surprisingly, pash-1ts mutants were resistant to chronic applications of ER stressors in detrimental concentrations, which normally lead to the activation of pro-apoptotic branch of UPRER. So that our data suggest a model in which the absence of miRNA production may confer resistance to the upregulation of apoptotic pathways upon ER stress although it needs to be further studied. We also showed that XBP-1s, a cell-non-autonomous regulator of UPRER leading to the extension of lifespan, exhibited no change in lifespan of the worms lacking miRNA production. These results suggest that pash-1ts animals can be used as a new tool to study miRNA functions in the non-autonomous cell signaling in the future.