depletion of the c. elegans nac engages the unfolded protein response, resulting in increased chaperone expression and apoptosis损耗的秀丽隐杆线虫nac展开的蛋白质反应,导致增加伴侣蛋白表达和细胞凋亡.pdfVIP

Depletion of the C. elegans NAC Engages the Unfolded Protein Response, Resulting in Increased Chaperone Expression and Apoptosis Paul T. Arsenovic, Anthony T. Maldonado, Vaughn D. Colleluori, Tim A. Bloss* Department of Biology, James Madison University, Harrisonburg, Virginia, United States of America Abstract The nascent polypeptide-associated complex (NAC) is a highly conserved heterodimer important for metazoan development, but its molecular function is not well understood. Recent evidence suggests the NAC is a component of the cytosolic chaperone network that interacts with ribosomal complexes and their emerging nascent peptides, such that the loss of the NAC in chaperone-depleted cells results in an increase in misfolded protein stress. We tested whether the NAC functions similarly in Caeonorhabditis (C.) elegans and found that its homologous NAC subunits, i.e. ICD-1 and -2, have chaperone-like characteristics. Loss of the NAC appears to induce misfolded protein stress in the ER triggering the unfolded protein response (UPR). Depletion of the NAC altered the response to heat stress, and led to an up-regulation of hsp-4, a homologue of the human chaperone and ER stress sensor GRP78/BiP. Worms lacking both ICD-1 and the UPR transcription factor XBP-1 generated a higher proportion of defective embryos, showed increased embryonic apoptosis and had a diminished survival rate relative to ICD-1-depleted animals with an intact UPR. Up-regulation of hsp-4 in NAC-depleted animals was specific to certain regions of the embryo; in embryos lacking ICD-1, the posterior region of the embryo showed strong up-regulation of hsp-4, while the anterior region did not. Furthermore, loss of ICD-1 produced prominent lysosomes in the gut region of adults and embryos putatively containing lipofuscins, lipid/pr