bims-unfpre 2024-10-13 papers

Issue of 2024‒10‒13
four papers selected by
Susan Logue, University of Manitoba

Org Biomol Chem. 2024 Oct 07.

Small molecules for impairing endoplasmic reticulum in cancer.

Tripti Mishra, Navneet Dubey, Sudipta Basu.

The endoplasmic reticulum plays an important role in maintaining the protein homeostasis of cells as well as regulating Ca2+ storage. An increased load of unfolded proteins in the endoplasmic reticulum due to alterations in the cell's metabolic pathway leads to the activation of the unfolded protein response, also known as ER stress. ER stress plays a major role in maintaining the growth and survival of various cancer cells, but persistent ER stress can also lead to cell death and hence can be a therapeutic pathway in the treatment of cancer. In this review, we focus on different types of small molecules that impair different ER stress sensors, the protein degradation machinery, and chaperone proteins. We also review the metal complexes and other miscellaneous compounds inducing ER stress through multiple mechanisms. Finally, we discuss the challenges in this emerging area of research and the potential direction of research to overcome them towards next-generation ER-targeted cancer therapy.

DOI: https://doi.org/10.1039/d4ob01238k

Life Sci. 2024 Oct 06. pii: S0024-3205(24)00702-1. [Epub ahead of print] 123112

Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy.

Li-Jen Soh, Siam-Yee Lee, Margaret M Roebuck, Pooi-Fong Wong.

Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.

Keywords: Endoplasmic reticulum stress; Inflammation; Osteoarthritis; Treatment strategy; Unfolded protein response; cGAS-STING signalling axis

DOI: https://doi.org/10.1016/j.lfs.2024.123112

Biochim Biophys Acta Mol Basis Dis. 2024 Oct 03. pii: S0925-4439(24)00527-1. [Epub ahead of print]1871(1): 167533

Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly.

Chao Yuan, Yanli Liao, WenXia Si, Mi Huang, Duanzhuo Li, Fuqing Wang, Yi Quan, Xin Yu, Shengjie Liao.

Endoplasmic reticulum-associated degradation (ERAD) serves as a crucial quality and quantity control system that removes misfolded or unassembled proteins from the Endoplasmic Reticulum (ER) through the cytoplasmic ubiquitin-proteasome system (UPS), which is critical for cell fate decision. ER stress arises when misfolded proteins accumulated within the ER lumen, potentially leading to cell death via proapoptotic unfolded protein response (UPR). UFD1 in associated with VCP-Npl4, is recognized as a key regulator of protein homeostasis in ERAD. However, the factors that control VCP complex assembly remain unclear. The study elucidates the function of Trim21, an E3 ubiquitin ligase, through its interaction with UFD1, facilitating K27-linkage ubiquitination of UFD1 and inhibiting its incorporation into the VCP complex. This results in the suppression of ERAD substrates degradation and the activation of a proapoptotic unfolded protein response in cancer cells. Additionally, Trim21 over-expression enhances ER stress response and promotes apoptosis upon expose to the ER inducer Tunicamycin. Notably, elevated Trim21 expression correlates with improved overall survival in various tumor types. Overall, the findings highlight the critical role of Trim21 in regulating ERAD progression and cell fate determination in cancer cells through modulation of VCP/Npl4/UFD1 complex assembly.

Keywords: Endoplasmic reticulum-associated degradation; Proapoptotic unfolded protein response; Trim21; UFD1; Ubiquitination

DOI: https://doi.org/10.1016/j.bbadis.2024.167533

Sci Rep. 2024 Oct 11. 14(1): 23812

Genetic knock-in of EIF2AK3 variants reveals differences in PERK activity in mouse liver and pancreas under endoplasmic reticulum stress.

Shivesh Ghura, Noah R Beratan, Xinglong Shi, Elena Alvarez-Periel, Sarah E Bond Newton, Cagla Akay-Espinoza, Kelly L Jordan-Sciutto.

Common single-nucleotide variants (SNVs) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) slightly increase the risk of disorders in the periphery and the central nervous system. EIF2AK3 encodes protein kinase RNA-like endoplasmic reticulum kinase (PERK), a key regulator of ER stress. Three exonic EIF2AK3 SNVs form the PERK-B haplotype, which is present in 28% of the global population. Importantly, the precise impact of these SNVs on PERK activity remains elusive. In this study, we demonstrate that PERK-B SNVs do not alter PERK expression or basal activity in vitro and in the novel triple knock-in mice expressing the exonic PERK-B SNVs in vivo. However, the kinase activity of PERK-B protein is higher than that of PERK-A in a cell-free assay and in mouse liver homogenates. Pancreatic tissue in PERK-B/B mice also exhibit increased susceptibility to apoptosis under acute ER stress. Monocyte-derived macrophages from PERK-B/B mice exhibit higher PERK activity than those from PERK-A/A mice, albeit with minimal functional consequences at acute timepoints. The subtle PERK-B-driven effects observed in liver and pancreas during acute stress implicate PERK as a contributor to disease susceptibility. The novel PERK-B mouse model provides valuable insights into ER stress-induced PERK activity, aiding the understanding of the genetic basis of disorders associated with ER stress.

Keywords: EIF2AK3 ; Endoplasmic reticulum; Haplotype; Protein kinase RNA-like ER kinase; Single-nucleotide variant; Stress; Unfolded protein response

DOI: https://doi.org/10.1038/s41598-024-74362-z