bims-ershed 2022-11-20 papers

Front Aging. 2022 ;3 1044556

IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.

Evandro A De-Souza, Nadia Cummins, Rebecca C Taylor.

The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPRER) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPRER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPRER activation with age. This underlines the mechanistic difference between age-associated loss of UPRER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.

Keywords: C. elegans; IRE1; UPR; aging; cell stress; proteostasis; stress response; unfolded protein response

DOI: https://doi.org/10.3389/fragi.2022.1044556

Cell Death Differ. 2022 Nov 15.

iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.

Shanliang Zheng, Xingwen Wang, Hao Liu, Dong Zhao, Qingyu Lin, Qinghua Jiang, Li Li, Ying Hu.

Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells' responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.

DOI: https://doi.org/10.1038/s41418-022-01086-w

Prog Lipid Res. 2022 Nov 13. pii: S0163-7827(22)00053-4. [Epub ahead of print]89 101198

Endoplasmic reticulum stress and lipids in health and diseases.

Cenk Celik, Stella Yue Ting Lee, Wei Sheng Yap, Guillaume Thibault.

The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.

Keywords: Cancer; Diabetes; Endoplasmic reticulum stress; Fatty liver; Immune response; Lipid bilayer stress; Lipid homeostasis; Lipotoxicity; Metabolic diseases; Unfolded protein response

DOI: https://doi.org/10.1016/j.plipres.2022.101198

Oxid Med Cell Longev. 2022 ;2022 4640161

Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity.

Yujing Zhang, Yuchen Qi, Shuai Huang, Xiaodong Jiang, Weiwei Xiao, Le Wang, Ziwei Liu, Sulai Liu.

The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.

DOI: https://doi.org/10.1155/2022/4640161