ATF6-mediated unfolded protein response

Definition

Target type: biologicalprocess

The series of molecular signals mediated by the endoplasmic reticulum membrane stress sensor ATF6 (activating transcription factor 6). Begins with activation of ATF6 in response to endoplasmic reticulum (ER) stress, and ends with regulation of a downstream cellular process, e.g. transcription. Under conditions of endoplasmic reticulum stress, ATF6 translocates to the Golgi where it is processed by proteases to release a cytoplasmic domain (ATF6f), which operates as a transcriptional activator of many genes required to restore folding capacity. [GOC:bf, GOC:PARL, PMID:22013210]

The ATF6-mediated unfolded protein response (UPR) is a crucial cellular signaling pathway that mitigates endoplasmic reticulum (ER) stress. When misfolded proteins accumulate in the ER lumen, ATF6 initiates a cascade of events to restore homeostasis. ATF6 is a transmembrane protein residing in the ER membrane. In its inactive state, it is bound to chaperone proteins like BiP/GRP78. Upon ER stress, BiP/GRP78 dissociates from ATF6, allowing its translocation to the Golgi apparatus. Within the Golgi, ATF6 undergoes proteolytic cleavage by S1P and S2P proteases, generating a cytosolic fragment containing the N-terminal domain. This fragment, ATF6(N), translocates to the nucleus and functions as a transcription factor. ATF6(N) binds to specific DNA sequences known as ER stress response elements (ERSEs) in the promoters of target genes. The activation of these genes results in the production of various proteins involved in protein folding, ER expansion, and ER-associated degradation (ERAD). These include chaperone proteins like BiP/GRP78 itself, protein disulfide isomerases (PDIs), and components of the ERAD machinery. Furthermore, ATF6 activates genes responsible for reducing protein synthesis, thereby decreasing the burden on the ER. By coordinating these cellular responses, ATF6-mediated UPR aims to alleviate ER stress and restore protein homeostasis. If the stress persists, prolonged ATF6 activation can trigger apoptosis, a programmed cell death mechanism, to eliminate severely compromised cells.'
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Proteins (2)

Compounds (1)