The Emerging Pathway of Misfolding-Induced ERS i...
In eukaryotic cells，the endoplasmic reticulum is essential for the folding and trafficking of secretory proteins.Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle，the accumulation of misfolded or unfolded proteins—known as ERS—and the activation of the adaptive unfolded protein response to restore homeostasis.However，misfolded proteins that result from heritable mutations may cause persistent ERS leading to genetic disease（Oakes and Papa 2015；Wang and Kaufman 2016）.(https://www.daowen.com)
That a subset of chronic pancreatitisassociated variants might exert their effect through misfolding-induced ERS was first suggested in 2009.Unlike some in vitro expressed PRSS1 mutants including p.Alal6Val，p.Asn291le，p.Asn29Thr and p.Arg122His which were secreted normally，the p.Argll6Cys mutant exhibited significant protein misfolding both in the test tube and in living cells；further，in cells expressing the p.Argl16Cys mutant，the ERS markers immunoglobulin-binding protein（BiP）and the spliced form of the X-box binding protein-1（XBP1s）were both elevated（Kereszturi et al.2009a）.Additional chronic pancreatitis-associated rare variants in the PRSS1 and CTRC genes were recently found to exert their effects in a way consistent with the misfolding-induced ERS mechanism（Beer et al.2013；Schnúr et al.2014）.Furthermore，defective CPA1 variants（see Sect.4）were often characterized by significantly decreased secretion，intracellular retention and degradation，implying involvement of misfolding-induced ERS；expression of the p.Asn256Lys variant，which was found in 7 chronic pancreatitis patients but not in controls，resulted in ERS in AR42J rat acinar cells（Witt et al.2013）.