What is activating transcription factor 6 (ATF6) used for?

Activating transcription factor 6 (ATF6) is a key transcription factor involved in the unfolded protein response (UPR) pathway, which is activated in response to endoplasmic reticulum (ER) stress. ATF6 is one of the three primary sensors of ER stress, along with inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK).

ATF6 is an ER transmembrane protein that resides in the ER under normal conditions. However, when the ER becomes stressed due to the accumulation of unfolded or misfolded proteins, ATF6 is translocated to the Golgi apparatus, where it undergoes proteolytic cleavage by Golgi-resident proteases, such as site-1 protease (S1P) and site-2 protease (S2P).

The cleavage of ATF6 releases its cytoplasmic domain, ATF6(N), which is a transcriptionally active fragment. ATF6(N) is then translocated to the nucleus, where it acts as a transcription factor by binding to specific DNA sequences called ER stress response elements (ERSE) or ER stress response element-like sequences (ERSE-II). It interacts with co-factors and activates the transcription of target genes involved in various aspects of the UPR and ER homeostasis.

The target genes regulated by ATF6 include those involved in ER protein folding, ER-associated degradation (ERAD), lipid metabolism, and ER membrane biogenesis. These genes help enhance the folding capacity of the ER, promote the degradation of misfolded proteins, and restore ER homeostasis. ATF6-mediated transcriptional activation contributes to cell survival and adaptation to ER stress.

ATF6 works in coordination with other UPR branches, such as IRE1 and PERK, to orchestrate the cellular response to ER stress. The three sensors of the UPR pathway act synergistically to restore ER function and promote cell survival. However, if the ER stress is prolonged or overwhelming, the UPR can trigger apoptosis, a programmed cell death pathway, to eliminate severely damaged cells that cannot recover from ER stress.

In summary, ATF6 is a transcription factor that is activated upon ER stress and regulates the expression of genes involved in ER protein folding, ERAD, lipid metabolism, and other processes necessary to alleviate ER stress and restore ER homeostasis.