Endocrine communication of endoplasmic reticulum stress.

Abstract

Cellular stress is caused by a multitude of environmental factors, which over the course of evolution have led to the development of molecular resistance programs.[1] Many of these are linked to the endoplasmic reticulum (ER), as the ER is the central platform for cellular lipid and protein synthesis. The unfolded protein response (UPR) is activated when partially folded or misfolded proteins accumulate in the lumen of the ER, typically referred to as ER stress. Through specific sensor proteins in the ER membrane, the cell can restore normal proteostasis by means of halted protein translation and enhanced folding machinery. However, if ER stress remains unresolved, sustained activation of UPR will ultimately result in cell death. In this issue of BioEssays, Watt et al. discuss UPR activation and the formation of bioactive lipids, proposing an endocrine role for ceramides in propagating UPR signaling to distant tissues.[2] There is evidence that ER stress is transmitted from stressed cells to healthy neighbors,[3] but the general view in the field is that cellular stress is communicated by cytokines (Figure 1). Undoubtedly, ER stress is associated with tissue inflammation and several lipid mediators are implicated in both initiation and resolution of inflammation. Over the past years, several bioactive lipids implicated in cell signaling have been described. Among these, ceramides are known to play a role in a variety of diseases, such as obesity, diabetes, hypertension, cancer, and COVID-19, where plasma and tissue levels of this sphingolipid are elevated. The detrimental effects of ceramides are associated with the disruption of intracellular signaling and induction of pro-inflammatory cytokine release. In terms of endocrine activity, ceramide action in the pathophysiology of diseases remains to be elucidated. This is complex because how ceramides are released or transported in the circulation is not well understood. Furthermore, dissociating ceramide action from inflammatory signaling might be difficult. It is noteworthy that while Watt et al. focus on discussing UPR as the main program combating ER stress,[2] proteostasis and the prevention and resolution of ER stress are critically dependent on the interplay of UPR, ER-associated protein degradation (ERAD), ubiquitin-proteasome system (UPS), and autophagy in a cell type-specific fashion.[1] It is still unclear how each of these programs compensate for each other but there is evidence that failure of one activates the others. For example, when UPS function is compromised, UPR and autophagy are activated, but this response is insufficient to restore proteostasis in the context of metabolic adaptation. Interestingly, failure of the UPS is associated with increased susceptibility to reactive oxygen species (ROS) and oxidative stress.[4] Especially in lipid-rich tissues or under conditions of dysregulated lipid metabolism such as obesity, ER stress could promote lipid peroxidation and local or distant tissue damage. In this context, one needs to consider that protein folding, one of the critical processes in the ER, is carried out in an oxidative environment to ensure the correct formation of disulfide bonds, which is very sensitive to changes in redox homeostasis. When ER stress is sustained, the increasing production of ROS drives the cell toward a state of oxidative stress. The unchecked production of ROS leads to the creation of oxilipid species, which have been described to have signaling functions,[5] but are also linked to ferroptosis, a non-apoptotic form of cell death induced by iron-dependent lipid peroxidation. Whether ER stress is directly linked to ferroptosis is poorly explored, but it is conceivable that sustained unresolved ER stress would promote ferroptosis. In fact, it has been recently shown that dysfunctional proteostasis is associated with increased susceptibility to ferroptosis.[4] How this local tissue damage response would be communicated in an endocrine fashion is unknown, but the hypothesis that ceramides or oxilipids play a role as lipokines here is intriguing. In conclusion, Watt et al. propose that bioactive lipids are extracellular communicators of ER stress. While this hypothesis is valid, more work is needed to provide causal proof of this concept. However, even if these lipids turn out to be biomarkers instead of causal lipokines they might still be useful for the early detection of diabetes and other diseases caused or promoted by ER stress. This article comments in the hypothesis paper by Nicole Watt, Anna McGrane, and Lee Roberts, https://doi.org/10.1002/bies.202300029. Alba Mena Gómez wrote the manuscript and created the figure with the help of Alexander Bartelt. All authors read and commented on the manuscript. Alexander Bartelt was supported by the German Center for Cardiovascular Research (DZHK), the DFG SPP2306 on ferroptosis, and the ERC Starting Grant PROTEOFIT. We apologize to colleagues whose work we could not cite due to space limitations. The authors declare no conflicts of interest.