Fig. 6
From: Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Involvement of ER stress in RP. The major pathogenetic process occurs in retinal cone and rod cells. The death of cone and rod occurs due to an imbalance between autophagy and ERAD. Impaired autophagy occurs through the P53-p38-MAPK-eIF4E cascade and is influenced by ATF4. In addition, ATF4 binds to key autophagy molecules LC3 and P62 to inhibit it. Proteasomes and lysosomes are responsible for clearing mutated protein, which is suppressed in RP. The ratio of autophagy: proteasome is decreased, which facilitates cone and rod cell death. ROS and Ca2+ can induce ER stress in RP. cdk5 is upregulated by ROS and Ca2+ and then stimulates the mekk1/JNK pathway, which promotes apoptosis. The IRE1α/ATF4/CHOP and ATF6 pathways influence caspase cascades and lead to apoptosis. ATF4 also influences p53 and then increases BH3 and Bad, which can lead to apoptosis directly and augment the mitochondrial permeability to facilitate apoptosis. RPE and blood-retinal-barrier (BRB) destruction are involved in the pathological process of RP. PRPF mutations cause the impaired autophagy and activated mTOR, which accelerate the photoreceptor outer segments. It is toxic for RPE. The accumulated PRPF protein accumulated in RPE induces apoptosis of RPE and destruction of BRB. The figure was created with BioRender.com (https://www.biorender.com/). RP retinitis pigmentosa, MAPK Mitogen-activated protein kinase, BRB blood-retinal-barrier, PRPF pre-mRNA processing factor, ERAD ER-associated degradation, ATF4 activating transcription factor 4, ATF6 activating transcription factor 6, eukaryotic translation initiation factor 2α (eIF2α), C/EBP-homologous protein (CHOP), PERK PKR-like ER kinase, IRE1 inositol requiring enzyme 1, XBP1 X-box binding protein 1