Department of Biology, James Madison University, Harrisonburg, Virginia, United States of America.
PLoS One. 2012;7(9):e44038. doi: 10.1371/journal.pone.0044038. Epub 2012 Sep 5.
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/protein aggregates associated with cellular aging. These results are the first set of evidence consistent with a role for C. elegans NAC in protein folding and localization during translation. Further, these findings confirm C. elegans as a valuable model for studying organismal and cell-type specific responses to misfolded protein stress.
新生多肽相关复合物（NAC）是一种高度保守的异二聚体，对后生动物的发育很重要，但它的分子功能尚不清楚。最近的证据表明，NAC 是细胞质伴侣网络的一个组成部分，与核糖体复合物及其新生的多肽相互作用，以至于在伴侣耗尽的细胞中失去 NAC 会导致错误折叠的蛋白质应激增加。我们测试了 NAC 是否在秀丽隐杆线虫（C. elegans）中具有类似的功能，发现其同源的 NAC 亚基，即 ICD-1 和 -2，具有伴侣样特征。NAC 的缺失似乎会在 ER 中诱导错误折叠的蛋白质应激，从而触发未折叠蛋白反应（UPR）。NAC 的耗竭改变了对热应激的反应，并导致 hsp-4 的上调，hsp-4 是人类伴侣和 ER 应激传感器 GRP78/BiP 的同源物。缺乏 ICD-1 和 UPR 转录因子 XBP-1 的线虫产生更多比例的缺陷胚胎，表现出更多的胚胎细胞凋亡，并且相对于具有完整 UPR 的 ICD-1 耗尽动物，存活率降低。NAC 耗尽动物中 hsp-4 的上调是胚胎特定区域特有的；在缺乏 ICD-1 的胚胎中，胚胎的后区显示出 hsp-4 的强烈上调，而前区则没有。此外，ICD-1 的缺失导致成虫和胚胎的肠道区域中出现明显的溶酶体，这些溶酶体可能含有脂褐素，即与细胞衰老相关的脂质/蛋白质聚集体。这些结果是第一组一致的证据，表明 C. elegans NAC 在翻译过程中参与蛋白质折叠和定位。此外，这些发现证实了 C. elegans 是研究折叠错误的蛋白质应激对生物体和细胞类型特异性反应的有价值的模型。
