Recent advances in small molecule and peptide inhibitors of glucose-regulated protein 78 for cancer therapy

Guo, Weikai; Wang, Manjie; Yang, Zhengfan; Liu, Danyang; Ma, Borui; Zhao, Yanqun; Chen, Yihua; Hu, Yanzhong

doi:10.1016/j.ejmech.2023.115792

Cited by 1 publication

(1 citation statement)

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“…GRP78 plays a key role: in normal conditions it is bound to PERK, eIF2 subunit alpha and ATF6 and inactivates these sensors. In stress conditions, it is overexpressed while being titrated by misfolded proteins, resulting in the release and activation of the three sensors [ 25 ]. ER stress occurs in several pathophysiological situations and diseases, including ischemic diseases [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Ribosomal Protein MRPS15 Is a Component of Cytosolic Ribosomes and Regulates Translation in Stressed Cardiomyocytes

David,

Roussel,

Froment

et al. 2024

IJMS

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Regulation of mRNA translation is a crucial step in controlling gene expression in stressed cells, impacting many pathologies, including heart ischemia. In recent years, ribosome heterogeneity has emerged as a key control mechanism driving the translation of subsets of mRNAs. In this study, we investigated variations in ribosome composition in human cardiomyocytes subjected to endoplasmic reticulum stress induced by tunicamycin treatment. Our findings demonstrate that this stress inhibits global translation in cardiomyocytes while activating internal ribosome entry site (IRES)-dependent translation. Analysis of translating ribosome composition in stressed and unstressed cardiomyocytes was conducted using mass spectrometry. We observed no significant changes in ribosomal protein composition, but several mitochondrial ribosomal proteins (MRPs) were identified in cytosolic polysomes, showing drastic variations between stressed and unstressed cells. The most notable increase in polysomes of stressed cells was observed in MRPS15. Its interaction with ribosomal proteins was confirmed by proximity ligation assay (PLA) and immunoprecipitation, suggesting its intrinsic role as a ribosomal component during stress. Knock-down or overexpression experiments of MRPS15 revealed its role as an activator of IRES-dependent translation. Furthermore, polysome profiling after immunoprecipitation with anti-MRPS15 antibody revealed that the “MRPS15 ribosome” is specialized in translating mRNAs involved in the unfolded protein response.

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Section: Introductionmentioning

confidence: 99%