ATF6 - monitoring and regulating protein folding under cellular stress

Mon, 06/01/2015 - 14:54

During times of cellular stress overloading of the protein folding machinery leads to the accumulation of incorrectly folded proteins. This triggers the unfolded protein response (UPR) in order to try to reestablish homeostasis or, if this fails, to induce apoptosis. The UPR pathway is mediated by a group of ER-associated transmembrane receptors including activating transcription factor 6 (ATF6). The presence of misfolded proteins is monitored by BiP, an Hsp70 family member. BiP functions as a chaperone protein and sensor by recognizing and binding to exposed hydrophobic stretches in unfolded proteins. Normally BiP is associated with membrane-bound ATF6 and retains it in the ER. Under cellular stress BiP disassociates and preferentially binds to misfolded proteins allowing ATF6 translocation to the Golgi. Once at the Golgi ATF6 is cleaved releasing a 50kD soluble transcriptional domain that translocates to the nucleus to regulate gene expression in order to increase chaperone activity and the degradation of unfolded proteins. In this way ATF6 is essential for monitoring and responding to stress to achieve protein folding homeostasis. Malfunctions in this pathway can have far-reaching effects and are involved in various diseases including diabetes and tumor progression.

The ATF6 antibody is heavily used to monitor ATF6 cleavage by western blotting as a marker for activation of the UPR. The Moore group from Baylor College of Medicine used this cleavage assay with the ATF6 antibody to monitor the UPR in their study published in eLife (1). In this study they identified an essential stress resolution pathway regulated by LRH-1 which functions independently of the UPR. The Jung group at the University of Munich also used ATF6 antibody to monitor ATF6 cleavage to monitor the UPR in colorectal tumor cells (2). They showed epithelial-mesenchymal transition is required to induce the ER stress response in tumor cells. This demonstrated a hierarchy in the steps of tumor progression in colorectal cancer. Wang et al. at the University of Chicago also used ATF6 antibody to monitor ATF6 cleavage in order to study the UPR in amyotrophic lateral sclerosis (ALS) (3). Misfolding and aggregation of mutant SOD1 is a cause of ALS. This study showed disruption of the UPR enhanced the accumulation of mutant SOD1 aggregates and enhanced disease onset. Rahmani et al. used the ATF6 antibody to characterize the mechanism of sorafenib, a kinase inhibitor that induces apoptosis of leukemia cells (4). The study showed full-length ATF6 diminishes after sorafenib treatment indicating induction of UPR. Blocking the UPR was able to reduce sorafenib-induced apoptosis.

Novus Biologicals offers ATF6 reagents for your research needs including:


  1. 24737860
  2. 24498091
  3. 21159797
  4. 17548474

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