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Abstract(s)
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and degrades mRNAs carrying premature translation-termination codons (PTCs), protecting the cell from potentially harmful truncated proteins (1). Recent studies demonstrated that NMD also targets mRNAs transcribed from a large subset of wild-type genes, arising as a mechanism of gene expression regulation (2,3). This raised the possibility that NMD is a controlled mechanism, an idea that was confirmed by recent studies, where NMD activity was seen to be modulated in specific cell types (4) and auto regulated through its intrinsic mechanism of mRNA degradation (5). Cellular stress, such as endoplasmic reticulum (ER) stress, hypoxia, reactive oxygen species, and nutrient deprivation were also seen to modulate the magnitude of NMD by mechanisms that are beginning to be understood (6). For example, the activation of kinases, as part of the cell-stress corrective pathways, induces the phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α), reducing protein translation and thus impairing NMD activity (7,8). In contrast, this eIF2α phosphorylation-dependent inhibition of NMD in stress conditions is responsible for the upregulation of many stress-related transcripts that are responsible for allowing the cell to cope with stress (7,9–11).
There is currently great interest in decoding the mechanisms that couple stress signaling to human pathology. Only recently has ER stress been considered a potential contributor to cardiac and vascular diseases (12). Myocardial infarction is a pathological state that occurs during ischemia, where there is nutrient and oxygen deprivation in the heart, causing aggregation of proteins in the ER. This aggregation triggers ER stress and the three arms (ATF6, IRE1α and PERK) of the unfolded protein response (UPR), to mitigate or eliminate the stress (12). Ultimately, if the stimulus is continued, cell death is activated (13,14). NMD plays a role in the regulation of the UPR, establishing a threshold for its activation and its time-dependent attenuation, that is accomplished, in part, through degradation of the IRE1α mRNA (9). NMD also protects the cell from death in response to stress, but the mechanism for this remains unclear (9).
Despite being a very well-studied mechanism, NMD and its role in cell physiology needs to be further explored. Given this and the all above-mentioned, the main goal of this project is to understand the role of NMD in the PERK-mediated response to ER stress induced by ischemia during myocardial infarction, and its impact to the pathophysiology of this disease. For this purpose, H9C2 cell line will be used as a model of cardiomyocytes, which will help us to dissect the crosstalk communication between NMD and UPR, through the PERK pathway, in myocardial infarction-mimicking conditions.
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Genómica funcional e estrutural Expressão génica