Table 3.

ATF6 signalling in tissue homeostasis and pathogenesis

Tissue	Model	Effect	Reference
Protective Role of ATF6 Signalling
Heart	Mouse model of myocardial ischemia/reperfusion damage KO of ATF6 in mice	When compared to wild-type tissue, ATF6 KO mouse cardiac tissue exhibited increased damage upon ischemia/reperfusion. Mechanistically, ATF6 upregulates oxidative stress genes, such as catalase, to exert cardioprotective effects in this context	[49]
Kidney	Tunicamycin-induced cytotoxicity in rat-derived glomerular epithelial cells (GECs)	Calcium-independent phospholipase A2γ (iPLA2γ) is protective against GEC injury. ATF6 contributes to iPLA2γ-mediated cytoprotection	[50]
Brain	Short-form ATF6 KI in forebrain neurons of mice (tamoxifen-inducible activation) Experimental model of stroke induced by middle cerebral artery occlusion	Forced activation of ATF6 reduced infarct volume and improved functional outcome following 24 h post-model induction	[51]
	R6/2 mouse model of Huntington’s disease	Derepression of ATF6 was associated with early neuroprotection in this model of Huntington’s disease	[52]
	Kainate-induced neurotoxicity in hippocampi of mice ATF6α KO	Kainate induced pronounced neuronal death in hippocampal CA3 region of ATF6α-KO mice. Hence, ATF6α protects against kainate-induced neurotoxicity in mice	[53]
Pancreas/Liver	Diet-induced obese mice KOt of ATF6α	ATF6α protects pancreatic β-cells from endoplasmic reticulum stress	[55]
	Zebrafish model of endoplasmic reticulum stress and fatty liver disease Depletion of active ATF6 through mutation in site-1 protease gene (mbtps1) or atf6 morpholino injection	ATF6 protects against hepatic steatosis following tunicamycin-induced acute endoplasmic reticulum stress	[57]
Pathological Role of ATF6 Signalling
Liver	OE of activated form of ATF6α in human hepatocellular carcinoma cell line (HLF)	ATF6α maylead to hepatocarcinogenesis by directly and indirectly regulating a broad range of genes associated with transformation	[46]
	Zebrafish model of endoplasmic reticulum stress and fatty liver disease; Depletion of active ATF6 through mutation in site-1 protease gene (mbtps1) or atf6 morpholino injection	ATF6 ➔ hepatic steatosis resulting from chronic endoplasmic reticulum stress	[57]
Squamous Epithelium	Quiescent human squamous carcinoma cells (D-HEp3 cells) KD of ATF6α expression in D-Hep3 cells using chick chorioallantoic membrane and nude mice for xenograft studies	ATF6α ➔ dormant cell survival, adaptation of dormant cells to chemotherapy, nutritional stress and the in vivo microenvironment ATF6α-Rheb-mTOR signalling ➔ survival and adaptation of carcinoma cells	[47]
Pancreas	Diet-induced obese mice KO of ATF6α	ATF6α ➔ development of hyperlipidaemia and insulin resistance in mouse model of diabetes	[55]
	Otsuka Long Evans Tokushima Fatty rat model of type II diabetes	↑ ATF6 in pancreatic islets in diseased rats; ATF6 ➔ ↓insulin levels	[56]

Key: ATF6 activating transcription factor 6, GEC glomerular epithelial cell, iPLA2γ calcium-independent phospholipase A2γ, KD knockdown, KI knockin, KO knockout