The Role of Endoplasmic Reticulum Stress in Autoimmune-Mediated Beta-Cell Destruction in Type 1 Diabetes

Table 1

Publications relevant to ER stress in the regulation of immune response and β-cell destruction.

Author	Defective/mutant gene	Species	Major finding	Reference
Harding et al.	PERK^−/−	Mouse	PERK-deficient mice are extremely susceptible to diabetes. They display a progressive β-cell loss and hyperglycemia with aging.	[49]
Delépine et al.	PERK^−/−	Human	Deficiency of PERK in human results in Wolcott-Rallison syndrome, which is characterized by early infancy insulin-dependent diabetes and multisystemic dysfunction.	[50]
Scheuner et al.	eIF2𝛼 mutant (Ser51Ala)	Mouse	Ser51Ala mutation of eIF2α shows a deficiency in pancreatic β cells manifested by the smaller core of insulin-secreting β cells and attenuated insulin secretion, and the mice die from hypoglycemia at their early infancy.	[52]
Ron et al.	Ins2 mutation	Mouse	Ins2 mutation in Akita mice disrupts disulfide bond between the α and β chain of proinsulin, which leads to the mis-folding of the mutated insulin and further induces ER stress in β cells and diabetes.	[56]
Zhang et al.	IRE1^−/−	Mouse	Pro-B cells failed to differentiate into pre-B cells when deficient for IRE1.	[65]
Iwakoshi et al.	XBP-1^−/−	Mouse	Deficiency of XBP-1 results in the impacted development of both conventional and plasmacytoid DCs. Loss of XBP-1 renders DCs vulnerable to ER stress-induced apoptosis.	[72]
Goodall et al.	CHOP knockdown		Knockdown of CHOP suppressed the production of IL-23 induced by ER stress and TLR signaling.	[73]
Richardson et al.	XBP-1 mutation	C. elegans	Innate immune response induced by P. aeruginosa infection causes ER stress in C. elegans, and mutations with loss of function for XBP-1 lead to larval lethality.	[74]
Kaser et al.	XBP-1 polymorphisms	Human	Loss of XBP-1 in intestinal epithelial cells induces Paneth cell dysfunction and overactive epithelium, leading to impaired mucosal defense to Listeria monocytogenes and increased sensitivity to colitis, an inflammatory disease sharing similar properties with T1D. The polymorphisms within the XBP-1 gene are associated with Crohn’s disease and ulcerative colitis in humans.	[75]
Nakagawa et al.	Caspase-12^−/−	Mouse	Caspase-12 is involved in ER stress-induced apoptosis. Mice deficient in caspase-12 are resistant to ER stress-induced apoptosis, but remain susceptible to apoptosis induced by other stimuli.	[96]
Hitomi et al.	Caspase-4 knockdown	Human	Human caspase-4, the closest paralog of rodent caspase-12, is involved in ER stress-induced apoptosis. Knockdown of caspase-4 by siRNA reduces ER stress-induced apoptosis.	[98]
Nishitoh et al.	Ask1^−/−	Mouse	Loss of Ask1 suppresses ER stress-induced JNK activation and protects cells from ER stress-induced death.	[103]