SUN-045 Resilience in the Regulation of the Unfolded Protein Response across Tissues and Species

The maintenance of homeostasis is fundamental for the efficient execution of all biological processes. A series of adaptive responses, pertinent to all scales of biological organization, have evolved to assist cells, tissues, organs and indeed individuals to attain homeostasis in response to stimuli that tend to abolish it. At the biochemical level a well appreciated such response is the unfolded protein response (UPR) that is triggered during stress of the endoplasmic reticulum (ER), a component of the integrated stress response. Common stimuli that may inflict ER stress are special diets, especially rich in calories and/or lipids, hypoxia, and even aging. While virtually all cells in every tissue and species are capable of inflicting the UPR during stress of the ER, little is known with regards to how this response operates across species, in genetically diverse individuals, or even different tissues of the same individual. By studying ER stress in cultured cells and tissues of genetically diverse animals of the genus Peromyscuswe started addressing these questions and explored their biological ramifications. We discovered that despite the fact that high variation exists between individuals in the expression levels of various UPR components (BiP, GRP94, calnexin, ATF4 and CHOP, a stunningly high degree of coordination is maintained between the expression of different chaperones, with some animals exhibiting uniformly high and others exhibiting moderate or lower response. Noteworthy, by comparing the UPR profile in tissues from a panel of genetic diverse P. leucopus we found that different tissues have their own resilience to stress. In example, despite the inherent variation, brain displayed the tightest coordination between the levels of expression of different chaperones that implies the lowest resilience which in turn is consistent with elevated demand of the tissue for increased homeostatic performance. In these studies, lungs exhibited moderate and the liver the lowest robustness in the degree of coordination in the chaperones examined which in turn may reflect moderate or high resilience for the corresponding tissue respectively. This is in line with each tissue’s ability to be in direct contact and to process exogenously inflicted, naturally occurring stimuli such as the breathing air or the food respectively. How factors such as aging or special diet affect the degree of coordination will be discussed. These results underscore the significance of coordination - as opposed to mere expression levels - and imply that the ability to adapt at different environments and indeed the susceptibility to disease may constitute reflections of the inherent resilience of different tissues in maintaining coordination of gene expression.