| Description |
The endoplasmic reticulum (ER) is a dynamic organelle that is responsible for the folding and quality control of proteins within the endomembrane system. Both physiological and pathological conditions can result in accumulation of misfolded proteins within the ER, a situation termed ER stress, which results in cell death if not alleviated. Perturbations in ER function result in activation of three ER transmembrane proteins (Ire1, Perk, and Atf6) that are primarily responsible for facilitating the unfolded protein response (UPR). Activation of the UPR initially increases ER capacity to offset the surge in misfolded protein; however, during irremediable stress, the UPR activates pro-apoptotic pathways presumably to prevent the cytotoxic consequences of secreting misfolded proteins. Ire1 is an endoribonuclease that is responsible for the unconventional splicing of an intron from the transcription factor, Xbp1. However, Ire1 is also responsible for the direct degradation of a number of mRNAs, a process termed regulated Ire1-dependent decay (RIDD). In mammals, long-term activation of Ire1 results in nonspecific cleavage of ER-localized mRNAs and subsequent cell death. However, at early time points a limited number of mRNAs are prioritized to the RIDD pathway and are degraded relatively rapidly. In the work presented here, I address the questions of (1) how specific mRNAs are prioritized for degradation? And (2) what is the function mRNA degradation during acute of ER stress? I have found that specific nucleotide sequence and structural motifs are used to target mRNAs to the RIDD pathway in both fly and mammalian cells. Furthermore, I show that inhibiting translation of these motifs is also essential for RIDD targeting. Lastly, I show Ire1-dependent effects on lysosome accumulation during ER stress; this may enhance prosurvival signaling of the UPR. These data provide insight into the mechanisms of Ire1 function as well as a model for how the RIDD pathway may function in both the prosurvival and pro-apoptotic pathways of the UPR. |
