A lifetime of stress: ATF6 in development and homeostasis

Robert F. Hillary, Una FitzGerald

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER)-localised protein and member of the leucine zipper family of transcription factors. Best known for its role in transducing signals linked to stress to the endoplasmic reticulum, the 50 kDa activated form of ATF6 is now emerging as a major regulator of organogenesis and tissue homeostasis. Responsible for the correct folding, secretion and membrane insertion of a third of the proteome in eukaryotic cells, the ER encompasses a dynamic, labyrinthine network of regulators, chaperones, foldases and cofactors. Such structures are crucial to the extensive protein synthesis required to undergo normal development and maintenance of tissue homeostasis. When an additional protein synthesis burden is placed on the ER, ATF6, in tandem with ER stress transducers inositol requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), slows the pace of protein translation and induces the production of stress-reducing chaperones and foldases. In the context of development and tissue homeostasis, however, distinct cellular impacts have been attributed to ATF6. Drawing on data published from human, rodent, fish, goat and bovine research, this review first focuses on ATF6-mediated regulation of osteo- and chondrogenesis, ocular development as well as neuro- and myelinogenesis. The purported role of ATF6 in development of the muscular and reproductive systems as well as adipo- and lipogenesis is then described. With relevance to cardiac disease, cancer and brain disorders, the importance of ATF6 in maintaining tissue homeostasis is the subject of the final section. In conclusion, the review encourages further elucidation of ATF6 regulatory operations during organogenesis and tissue homeostasis, to spawn the development of ATF6-targeted therapeutic strategies.