Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution

Abstract

Considerable progress has been made in understanding the physiological basis for variation in the life‐history patterns of animals, particularly with regard to the roles of oxidative stress and hormonal regulation. However, an underappreciated and understudied area that could play a role in mediating inter‐ and intraspecific variation of life history is endoplasmic reticulum (ER) stress, and the resulting unfolded protein response (UPRER). ER stress response and the UPRER maintain proteostasis in cells by reducing the intracellular load of secretory proteins and enhancing protein folding capacity or initiating apoptosis in cells that cannot recover. Proper modulation of the ER stress response and execution of the UPRER allow animals to respond to intracellular and extracellular stressors and adapt to constantly changing environments. ER stress responses are heritable and there is considerable individual variation in UPRER phenotype in animals, suggesting that ER stress and UPRER phenotype can be subjected to natural selection. The variation in UPRER phenotype presumably reflects the way animals respond to ER stress and environmental challenges. Most of what we know about ER stress and the UPRER in animals has either come from biomedical studies using cell culture or from experiments involving conventional laboratory or agriculturally important models that exhibit limited genetic diversity. Furthermore, these studies involve the assessment of experimentally induced qualitative changes in gene expression as opposed to the quantitative variations that occur in naturally existing populations. Almost all of these studies were conducted in controlled settings that are often quite different from the conditions animals experience in nature. Herein, we review studies that investigated ER stress and the UPRER in relation to key life‐history traits including growth and development, reproduction, bioenergetics and physical performance, and ageing and senescence. We then ask if these studies can inform us about the role of ER stress and the UPRER in mediating the aforementioned life‐history traits in free‐living animals. We propose that there is a need to conduct experiments pertaining to ER stress and the UPRER in ecologically relevant settings, to characterize variation in ER stress and the UPRER in free‐living animals, and to relate the observed variation to key life‐history traits. We urge others to integrate multiple physiological systems and investigate how interactions between ER stress and oxidative stress shape life‐history trade‐offs in free‐living animals.

Xbp1 and Brachyury establish an evolutionarily conserved subcircuit of the notochord gene regulatory network

“…Among them is the Ciona counterpart of X-box binding protein 1 (Xbp1) ( Kugler et al, 2008 ), a basic leucine-zipper transcription factor that regulates the unfolded protein response (UPR) ( Mai and Breeden, 1997 ; Yoshida et al, 2001 ). The UPR of the endoplasmic reticulum (ER) is an evolutionarily conserved mechanism that allows cells to counteract the stress caused by the presence of improperly folded proteins in the ER ( Yap et al, 2021 ). Three ER-stress sensors, Ire1, Perk, and Atf6, are responsible, in metazoans, for the activation of the transcription factors Xbp1, Atf4, and Atf6-alpha, respectively ( Hollien, 2013 ; Mitra and Ryoo, 2019 ).…”

Traditional Chinese medicine prescription Shenling BaiZhu powder to treat ulcerative colitis: Clinical evidence and potential mechanisms

“…UPR can disaggregate the three proteins from GRP78, thus receiving and inhibiting ERs through the IREl-XBP1 pathway, PERK-el F2α-ATF-4 pathway, and ATF-6 pathway. In addition, the CHOP pathway, IRE1-TRAF2-ASK1 pathway, and caspase pathway are pathways mediated by ERs and lead to cell apoptosis ( Yap et al, 2021 ). ERs as a regulation mechanism widely exist in the body, which similarly plays an essential role in the pathological process of IBD ( Bogaert et al, 2011 ).…”

Relocation to avoid costs: A hypothesis on red carotenoid‐based signals based on recent CYP2J19 gene expression data

“…fucoxanthin, explored as a drug) was found to be transformed in hepatic microsomes of mice (Asai et al 2004). Nevertheless, bimodal expression (both at the mitochondrion and ER) has also been demonstrated for some CYPs (Avadhani et al 2011), and a tight cross-talk between both organelles exists (Yap et al 2021). If the CYP2J19 enzyme is, alternatively or additionally, present in ER, the mechanistic interpretations about signal reliability should be revisited.…”