The Ca2+‐binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6
Year: 2021
Type: article
Abstract: ABSTRACT Levels of the transcription factor ATF6α, a key mediator of the unfolded protein response, that provides cellular protection during the progression endoplasmic reticulum (ER) stress, are markedly reduced in the pancreatic islet of patients with type 2 diabetes and in rodent models of the disease, including ob/ob and high fat-fed mice. Sorcin (gene name SRI ) is a calcium (Ca 2+ ) binding protein involved in maintaining ER Ca 2+ homeostasis. We have previously shown that overexpressing sorcin under the rat insulin promoter in transgenic mice was protective against high fat diet-induced pancreatic beta cell dysfunction, namely preserving intracellular Ca 2+ homeostasis and glucose-stimulated insulin secretion during lipotoxic stress. Additionally, sorcin overexpression was apparently activating ATF6 signalling in MIN6 cells despite lowering ER stress. Here, in order to investigate further the relationship between sorcin and ATF6, we describe changes in sorcin expression during ER and lipotoxic stress and changes in ATF6 signalling after sorcin overexpression or inactivation, both in excitable and non-excitable cells. Sorcin mRNA levels were significantly increased in response to the ER stress-inducing agents thapsigargin and tunicamycin, but not by palmitate. On the contrary, palmitate caused a significant decrease in sorcin expression as assessed by both qRT-PCR and Western blotting despite inducing ER stress. Moreover, palmitate prevented the increase in sorcin expression induced by thapsigargin. In addition, sorcin overexpression significantly increased ATF6 transcriptional activity, whereas sorcin inactivation decreased ATF6 signalling. Finally, sorcin overexpression increased levels of ATF6 immunoreactivity and FRET imaging experiments following ER stress induction by thapsigargin showed a direct sorcin-ATF6 interaction. Altogether, our data suggest that sorcin down-regulation during lipotoxicity may prevent full ATF6 activation and a normal UPR during the progression of obesity and insulin resistance, contributing to beta cell failure and type 2 diabetes.
Source: FEBS Letters
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,300
Awards: G113165498, Investigating the role of immature beta cells in insulin release from the intact islet, G130968091, G1335979935, Genetic and nutritional control of pancreatic beta cell identity., G1937207371, Roles of GWA genes in controlling pancreatic beta cell function and mass., G2040450235, G3555667338, G4426574518, G4781795914, All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease, G5482254092, G5673545276, The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function, G6133425169, Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes, Understanding pancreatic beta cell connectivity, Molecular mechanisms linking Sorcin to pancreatic beta cell lipotoxicity and ER Ca2+ stores., G7571465722, Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse, G8479309682, G8635620823, G8897119323, G9000168923, Does the calcium sensor sorcin protect against glucolipotoxicity and beta cell failure in Type 2 diabetes?
OpenAlex ID: W3158593281