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n a new study published in this issue of Cellular Iand Molecular Gastroenterology and Hepatology, Waldron et al used proteomic approaches to define how ethanol modifies the redox state of the pancreas ER proteome. These structural changes and ER dysfunction may contribute to ethanol-induced pathology associated with pancreatitis. Alcoholic pancreatitis is one of the major forms of acute and chronic pancreatitis. Although heavy alcohol use is a major risk factor for pancreatitis, not all individuals with long-term alcohol use develop pancreatic injury and disease. Instead, it is believed that alcohol sensitizes the pancreas to other stressors that trigger disease pathogenesis. Understanding exactly how alcohol sensitizes the pancreas to injury is an active area of investigation. Key drivers of pancreatitis are defects in exocrine acinar cells. Acinar cells are highly specialized secretory cells that produce large quantities of digestive enzymes. These proteins are synthesized in the endoplasmic reticulum (ER) and are targeted to the cell surface for secretion via the secretory pathway. When defects in protein folding occur as a result of genetic mutations, increased secretory demand, or oxidative damage, and unfolded proteins accumulate and trigger ER stress. Mammalian cells have evolved an integrated set of signaling pathways to manage ER stress via the unfolded protein response (UPR). The UPR acts to slow translation, aid in protein folding, and target misfolded proteins for degradation. The ultimate goal is to restore proteostasis. However, in the case of unabated ER stress, cells bypass the adaptive UPR and activate cell death programs. ER dysfunction in acinar cells is believed to be a primary contributor to alcohol-induced pancreatitis. In mice, for example, chronic ethanol feeding triggers a UPR. The UPR in this case is an adaptive response that allows the cell to deal with ethanol-induced damage. In the absence of the transcription factor X-box binding protein 1 (XBP1)—a key mediator of the UPR—acinar cells are unable to resolve ER stress from ethanol feeding resulting in acinar cell death. These results suggest that an impaired UPR contributes to ER dysfunction and acinar cell pathology, which might play a role in the pathophysiology of alcoholic pancreatitis. Although impaired UPR signaling and ER dysfunction are drivers of ethanol-induced pancreas pathology, it is unknown what structural changes or folding defects contribute to ER stress. To address this problem, Waldron et al used elegant proteomic approaches to define the structural changes that take place in the ER after ethanol

Proteomic Study Defines How Alcohol Alters ER Structure and Redox Proteome to Trigger ER Stress and Acinar Cell Pathology in Pancreatitis