From endoplasmic-reticulum stress to the inflammatory response

The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62741/1/nature07203.pd

Age-Related Tooth Wear Differs between Forest and Savanna Primates

Tooth wear in primates is caused by aging and ecological factors. However, comparative data that would allow us to delineate the contribution of each of these factors are lacking. Here, we contrast age-dependent molar tooth wear by scoring percent of dentine exposure (PDE) in two wild African primate populations from Gabonese forest and Kenyan savanna habitats. We found that forest-dwelling mandrills exhibited significantly higher PDE with age than savanna yellow baboons. Mandrills mainly feed on large tough food items, such as hard-shell fruits, and inhabit an ecosystem with a high presence of mineral quartz. By contrast, baboons consume large amounts of exogenous grit that adheres to underground storage organs but the proportion of quartz in the soils where baboons live is low. Our results support the hypothesis that not only age but also physical food properties and soil composition, particularly quartz richness, are factors that significantly impact tooth wear. We further propose that the accelerated dental wear in mandrills resulting in flatter molars with old age may represent an adaptation to process hard food items present in their environment

Isoform-selective ATAD2 chemical probe with novel chemical structure and unusual mode of action

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology

A novel disulphide switch mechanism in Ero1α balances ER oxidation in human cells

Oxidative maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is powered by Ero1 oxidases. To prevent cellular hyperoxidation, Ero1 activity can be regulated by intramolecular disulphide switches. Here, we determine the redox-driven shutdown mechanism of Ero1α, the housekeeping Ero1 enzyme in human cells. We show that functional silencing of Ero1α in cells arises from the formation of a disulphide bond—identified by mass spectrometry—between the active-site Cys94 (connected to Cys99 in the active enzyme) and Cys131. Competition between substrate thiols and Cys131 creates a feedback loop where activation of Ero1α is linked to the availability of its substrate, reduced protein disulphide isomerase (PDI). Overexpression of Ero1α-Cys131Ala or the isoform Ero1β, which does not have an equivalent disulphide switch, leads to augmented ER oxidation. These data reveal a novel regulatory feedback system where PDI emerges as a central regulator of ER redox homoeostasis