Atf6, an endoplasmic reticulum (ER)-localised protein and member of the leucine zipper family of transcription factors, is a key player in the ER unfolded protein response (UPR). When misfolded proteins accumulate in the ER, Atf6 is cleaved by Site-1 protease (S1P) and Site-2 protease (S2P), and its cytoplasmic domain enters the nucleus to induce genes encoding ER proteins for protein-folding, thus maintaining proteostasis [2,3]. It also has a role in many biological processes like development and tissue homeostasis [5].

In a severe acute pancreatitis (SAP) mouse model, knockout of Atf6 attenuated acinar injury, apoptosis and ER disorder. ATF6 was found to promote AIFM2 transcription by binding to p53 and AIFM2 promoters, indicating that the ATF6/p53/AIFM2 pathway plays a critical role in acinar apoptosis during SAP progression [1]. In intestinal-specific Pcdh20 knockout mice, colitis was aggravated due to disrupted barrier integrity. Administration of a selective ATF6 activator reversed the impairment of intestinal barrier integrity, suggesting that PCDH20 protects against colitis through the ATF6/CHOP/β-catenin/p-p120-catenin axis [4].

In conclusion, Atf6 is essential for maintaining proteostasis in cells, especially in the context of ER stress. Studies using knockout mouse models have revealed its significance in diseases such as severe acute pancreatitis and colitis. These findings highlight Atf6 as a potential therapeutic target in these disease areas [1,4].

References:

1. Tan, Jie-Hui, Cao, Rong-Chang, Zhou, Lei, Jin, Jin, Zhang, Guo-Wei. 2020. ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. In Theranostics, 10, 8298-8314. doi:10.7150/thno.46934. https://pubmed.ncbi.nlm.nih.gov/32724472/

2. Yoshida, H, Matsui, T, Yamamoto, A, Okada, T, Mori, K. . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. In Cell, 107, 881-91. doi:. https://pubmed.ncbi.nlm.nih.gov/11779464/

3. Ye, J, Rawson, R B, Komuro, R, Brown, M S, Goldstein, J L. . ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. In Molecular cell, 6, 1355-64. doi:. https://pubmed.ncbi.nlm.nih.gov/11163209/

4. Huang, Shanshan, Xie, Zhuo, Han, Jing, Chen, Minhu, Zhang, Shenghong. 2023. Protocadherin 20 maintains intestinal barrier function to protect against Crohn's disease by targeting ATF6. In Genome biology, 24, 159. doi:10.1186/s13059-023-02991-0. https://pubmed.ncbi.nlm.nih.gov/37407995/

5. Hillary, Robert F, FitzGerald, Una. 2018. A lifetime of stress: ATF6 in development and homeostasis. In Journal of biomedical science, 25, 48. doi:10.1186/s12929-018-0453-1. https://pubmed.ncbi.nlm.nih.gov/29801500/