ER Stress: From Cellular Surveillance to Disease Pathogenesis

Proteostasis is the basis of cell survival. As the primary site of protein synthesis and processing in eukaryotes, the endoplasmic reticulum (ER) highly selectively monitors the entry of various incorrectly folded proteins (including misfolded and unfolded proteins) into the cell surface. The machinery responsible for maintaining proteostasis includes molecular chaperones (such as BiP/Grp78 and Grp94), ATPases, and two major proteolytic systems: the ubiquitin-proteasome system and the autophagy-lysosome system. Misfolded proteins generated under stress conditions can be eliminated via the ER-associated degradation (ERAD) pathway. This process involves several key steps: substrate recognition by molecular chaperones and lectins within the ER lumen; subsequent dislocation across the ER membrane, a process driven by the VCP/p97 complex; polyubiquitination by specific E3 ubiquitin ligases in the cytosol; and final degradation by the 26S proteasome. Alternatively, aggregates of misfolded proteins or damaged ER fragments can be transported into the lysosome for degradation via autophagic pathways, including chaperone-mediated autophagy, microautophagy, and macroautophagy^[1].

When these proteins accumulate excessively in the ER, they disrupt the ER function, causing endoplasmic reticulum stress (ERS) and triggering the unfolded protein response (UPR) to reduce the burden on the ER and restore ER homeostasis. The UPR is regulated by three ER sensors: inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). They remain inactive when bound by the ER chaperone BiP (Grp78) but are activated upon BiP dissociation which initiates the UPR. Typical target genes of UPR can be correlated with protein folding, ER-associated degradation (ERAD), oxidative stress, autophagy, mitochondrial dysfunction, and metabolic pathways, with their induction varying by different tissues^[2].

However, the pathological impairment or excessive activation of ER stress induces protein synthesis inhibition, regulation of gene expression and cell fate decisions like apoptosis, triggering diseases in multiple fields, including metabolic, neurodegenerative, cardiovascular and inflammatory disorders as well as cancers.

Current therapeutic strategies for ERS include chemotherapy, natural compound therapy, stem cell therapy, and gene therapy. The chemical chaperones 4-Phenylbutyric acid (4-PBA) and Tauroursodeoxycholic Acid (TUDCA) improve protein folding ability. The natural compounds such as L-glutamine and glycine can reduce ERS-induced intestinal epithelial cell apoptosis. Moreover, the berberine and curcumin have great potential to inhibit excessive ERS. In the future, iPSCs, MSCs, and their exosomes are promising for reducing ERS through leverage precise homing. Furthermore, gene editing technologies like CRISPR/Cas9 and RNA splicing technology may be used to repair and alter ERS-related genes like XBP1 and IRE1, providing a fundamental solution to genetic diseases^[3][4].