![]() Proteasome, a large protein complex that usually localizes in the cytosol and nucleus, recognizes and degrades unfolded or misfolded proteins tagged with polyubiquitin. This has been associated with the pathogeneses of protein-misfolding diseases, including the Alzheimer’s disease and diabetes 14. When these adaptation mechanisms cannot remove the accumulated misfolded proteins sufficiently, cells undergo apoptosis. IRE1 is subsequently phosphorylated by oligomerization, activating endoribonuclease functions required to generate the active form of transcriptional factor XBP1s 13. Its cytosolic domain is released from the Golgi membrane and translocated into the nucleus, inducing its target genes encoding ER chaperones 12. Next, ATF6 is translocated from the ER to the Golgi and then cleaved by site-1 protease (S1P) and site-2 protease (S2P) 12. The UPR is activated by three ER stress sensors, PERK, ATF6 and IRE1 9, which are successively activated PERK is first dimerized and phosphorylated, inducing phosphorylation of eIF2α to suppress the general mRNA translation except for the translation of transcriptional factors such as ATF4 10, 11. ER stress activates adaptive cellular response called unfolded protein response (UPR) 8, which integrates signal transduction pathways that restore the aberration in ER proteostasis. When stresses exceed the capacity of ER protein quality control system, misfolded proteins accumulate in the ER, a condition referred to as ER stress. Therefore, it can be easily assumed that to maintain ER redox homeostasis is essential for protein quality control in the ER. Most of the proteins folded and maturated in ER have intra- and/or intermolecular disulfide bonds that are required for their folding and functions, whereas disulfide bond(s) of terminally misfolded proteins in the ER are reduced by the ER-resident reductase ERdj5 followed by retrotranslocation upon ERAD 6, 7. This process is called ER-associated degradation (ERAD).ĮR maintains an oxidative environment suitable for oxidative protein folding 5. Misfolded proteins are retained and refolded in the ER, and terminally misfolded proteins are retrotranslocated to the cytosol, and degraded by the ubiquitin–proteasome system 3, 4. Correctly folded proteins exit from the ER and are transported to the Golgi apparatus. Polypeptides newly synthesized in the ER are folded with the help of molecular chaperones and oxidoreductases such as BiP and protein disulfide isomerase (PDI) family proteins 1, 2. Endoplasmic reticulum (ER) is an organelle responsible for folding and maturation of secretory and membrane proteins, which amount to one third of synthesized proteins.
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |