Roles for ATF6 and the sarco/endoplasmic reticulum protein quality control system in the heart

The hypertrophic growth of cardiac myocytes is a highly dynamic process that underlies physiological and pathological adaptation of the heart. Accordingly, a better understanding of the molecular underpinnings of cardiac myocyte hypertrophy is required in order to fully appreciate the causes and functional consequences of the changes in the size of the healthy and diseased heart. Hypertrophy is driven by increases in cardiac myocyte protein, which must be balanced by cellular ability to maintain protein quality in order to avoid maladaptive accumulation of toxic misfolded proteins. Recent studies have shown that the endoplasmic reticulum (ER), which, in cardiac myocytes, comprises the sarco/endoplasmic reticulum (SR/ER), is the site of most protein synthesis. Thus, the protein quality control machinery located at the SR/ER is likely to be an important determinant of whether the heart responds adaptively to hypertrophic growth stimuli. The SR/ER-transmembrane protein, ATF6, serves a critical protein quality control function as a first responder to the accumulation of potentially toxic, misfolded proteins. Misfolded proteins transform ATF6 into a transcription factor that regulates a gene program that is partly responsible for enhancing protein quality control. Two ATF6-inducible genes that have been studied in the heart and shown to be adaptive are RCAN1 and Derl3, which encode proteins that decrease protein-folding demand, and enhance degradation of misfolded proteins, respectively. Thus, the ATF6-regulated SR/ER protein quality control system is important for maintaining protein quality during growth, making ATF6, and other components of the system, potentially attractive targets for the therapeutic management pathological cardiac hypertrophy. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".