**3. Protein quality control system (PQC)**

Protein quality control system ensures proper folding of proteins and degradation of the unfolded and partially folded proteins. Usually, the PQC system has the ability to eliminate defective ribosomal products, which have been synthesized as a result of errors in translation or post-translational processes or proteins. Protein quality control system comprises of endoplasmic reticulum-associated degradation, ubiquitin protease pathway, autophagy, and chaperones, which are activated countering misfolded protein and either slow their formation in order to either correct the misfolded protein and refold them or destruct the misfolded protein.

#### **3.1 Endoplasmic reticulum (ER)**

Endoplasmic reticulum (ER), besides being a major site for protein production, is one of the major cellular organelles involved in protein homeostasis and quality control. Cellular proteins utilize the ER to attain their folded and posttranslationally modified active state [23]. Although the ER is well furnished for synthesis and folding of significantly high amount of proteins, genetic or environmental alterations are known to stress out the ER promoting misfolding and accumulation of proteins. Unfolded protein response (UPR) mechanism utilized by ER to combat against protein misfolding. UPR is composed of three different transmembrane proteins, including ATF6 (activated transcription factor 6), PERK (double-stranded RNA activated protein kinase, such as ER kinase), and IRE1 (inositol-requiring transmembrane kinase and endonuclease). PERK blocks protein translation by phosphorylating eukaryotic translation initiation (eIF2), and ATF6 (p50ATF6) acts as transcription factor to induce expression of ER-resident chaperones, such as binding protein (BiP). IRE1 alternatively splices XBP1 mRNA. The activation of all three proximal sensors results in the attenuation of protein synthesis through eukaryotic initiation factor-2 (eIF2) kinase and increases protein-folding capacity of the ER. The spliced gene product induces transcription of different genes involved in the ER-associated degradation (ERAD) pathway [24].

The goals of the UPR involve shutting down further protein synthesis to reduce the overload of the ER, secondly, induce ER-resident chaperones to prevent misfolding, and lastly activate ER-associated degradation (ERAD) (IRE1pathway) system to shed off misfolded protein burden using the proteasome. While temporary stress is effectively handled by the UPR, chronic stress leads to continuous accumulation of misfolded protein beyond the capacity of the UPR regulation.
