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ATF6
ATF6 Full Name
activating transcription factor 6
ATF6 Introduction
ATF6 is one of the three major branches of the signal transduction pathways of the ER stress response, also known as the unfolded protein response (UPR). The unfolded protein response (UPR) is triggered in response to ER stress to reestablish cellular ER homeostasis by attenuating protein translation, upregulating the production of molecular chaperones that promote protein folding and upregulating the degradation of misfolded proteins. ATF6, IRE1α (inositol-requiring enzyme 1α) and PERK (PKR-like ER kinase) pathways form a regulatory network for UPR. ATF6 is a type II transmembrane glycoprotein. The N-terminus of ATF6 is located in the cytoplasm and contains a basic leucine zipper (bZIP) domain, the functional basis of the protein as a transcription factor. The C-terminus of ATF6 faces the lumen of the ER. Under physiological conditions, ATF6 is kept in an inactive form by binding to the chaperone protein BiP (also known as GRP78) in its luminal domain and tethered to the ER membrane. When unfolded proteins accumulate under ER stress conditions, these unfolded proteins bind competitively to BiP, which results in BiP dissociation from ATF6, and this is the initial trigger to activate ATF6. The activation of ATF6 is characterized by its transportation from the ER to the Golgi apparatus.
Figure 1. ATF6 is activated in response to ER stress through a process involving regulated proteolysis. (Source: Glembotski CC, et al. 2019)
In the Golgi, ATF6 is further processed in two proteolytic steps. The first cleavage is by Site-1 Protease (S1P) in the lumenal domain, followed by a second cleavage in its transmembrane domain by Site-2 Protease (S2P). The precise cascade of proteolytic processing events in the Golgi results in the release of the N-terminal cytoplasmic fragment of ATF6 (ATF6-N, also known as p50ATF6). The active N-terminal cytosolic fragment of ATF6 then translocates into the nucleus, where it binds as a transcription factor to ER stress response elements (ERSEs) in the promoter regions of target genes and activates the transcription of a large number of downstream genes, which mainly encode proteins involved in protein folding (BiP/GRP78, GRP94), protein disulfide bond formation (e.g. PDI) and ERAD (e.g. EDEM1, XBP1s). In this way, the ATF6 pathway robustly upregulates the protein folding capacity of the ER and is one of the major adaptive responses that a cell can utilize to restore ER homeostasis and promote survival.
On the contrary, moderate activation of ATF6 plays a crucial cytoprotective role during the early stage of many diseases or under certain conditions. In cardiovascular diseases, for instance, it has been reported that the activation of ATF6 can relieve myocardial ischemia/reperfusion injury, protect cardiomyocytes by upregulating chaperone proteins, inhibit apoptosis and so on, thereby maintaining cardiac function after myocardial infarction. In neurodegenerative diseases such as Alzheimer's disease (AD), the activation of ATF6 has been found to decrease the level of β-amyloid (Aβ) and protect the function of spatial memory in hippocampus, indicating that the activation of ATF6 may be a potential therapeutic target for AD. On the other hand, when ER stress is too strong or persistent for a cell to deal with, the function of ATF6 pathway may be changed. Prolonged activation of ATF6 can lead to cell apoptosis and thereby aggravate tissue damage. In metabolic diseases such as type 2 diabetes, sustained high glucose/high-fat stress in pancreatic β-cells can cause strong ER stress, and persistent ATF6 activation can eventually lead to β-cell apoptosis and cause insulin secretory dysfunction. In skeletal diseases such as osteoarthritis, studies have shown that ER stress and dysregulated ATF6 signaling in chondrocytes can promote chondrocyte apoptosis and matrix degradation, thus promoting disease progression. Mutations in the ATF6 gene that lead to loss of function cause hereditary retinal diseases such as achromatopsia and cone-rod dystrophy. Patients with achromatopsia have a total loss of cone photoreceptor function, so they are completely color blind, and have low vision and light sensitivity. The pathogenesis of the disease caused by ATF6 mutation lies in the fact that retinal photoreceptor cells, especially cone cells, need to synthesize and fold a very large amount of visual proteins (such as opsins) to form, which places a very high demand on ER function. As an important regulator of UPR, when such cells with ATF6 gene mutations are faced with the physiological or pathological protein folding load, their ability to trigger the adaptive stress response will be impaired, leading to the accumulation of unfolded proteins, resulting in cell dysfunction and eventually apoptosis, and leading to progressive degeneration of the retina.
Alternate Names for ATF6
ATF6; activating transcription factor 6; ATF6A; cyclic AMP-dependent transcription factor ATF-6 alpha; cAMP-dependent transcription factor ATF-6 alpha;
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