Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Abstract

The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.

PIKFYVE inhibitors trigger interleukin‐24‐dependent cell death of autophagy‐dependent melanoma

“…In addition to IL24, eight genes in the ‘PERK‐dependent ER‐stress response’ [ 41 , 42 ] were also transcriptionally upregulated: DDIT3/CHOP , PPP1R15A/GADD34 , GADD45A , MAPK13/p38d , CDKN1A/p21 , PMAIP/NOXA , BAK1/CDN1 , and BBC3/PUMA (Fig. S2B ).…”

Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons

“…We also recognized the limitations of our study. For example, the long-term inhibition of autophagy function through deletion of the essential autophagy genes may cause compensatory responses with specific changes in certain accumulated proteins resulting from disturbing cellular homeostatic mechanisms, such as ER stress, post-transcriptional modifications, and protein synthesis, etc 75 . Our approaches, however, is unable to exclude those proteins with increased levels caused potentially by the above conditions.…”

(+)-Catechin ameliorates diabetic nephropathy injury by inhibiting endoplasmic reticulum stress-related NLRP3-mediated inflammation

“…Mitochondria dysfunction can result in NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation, oxidative stress, and ER stress. 15 Furthermore, accumulating evidence suggests that ER stress can mediate NLRP3 inflammasome activation, which is a critical factor associated with sterile inflammation during DN. 16–19 The activation of NLRP3 can promote pro-caspase-1 self-cleavage and the secretion of interleukin 1β (IL-1β) and interleukin 18 (IL-18), leading to inflammation and even cell death.…”