Review Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy, 2025, Lee

[SNT Gatchaman]

Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy
Lee; Amy S

Since their discoveries in the 1960s as a family of proteins produced by cells in response to stress, molecular chaperones are increasingly recognized as major regulators of cellular homeostasis in health and disease. Among the heat shock protein 70 family, the 78-kDa glucose-regulated protein (GRP78), also referred to as BiP and encoded by the HSPA5 gene, contains a signal peptide targeting it into the endoplasmic reticulum (ER). Through its interaction with the transmembrane ER stress sensors, GRP78 acts as a master regulator of the Unfolded Protein Response (UPR) which allows cells to adapt to stress observed in many human diseases.

The discovery that ER stress not only upregulates GRP78 to cope with ER protein quality control but also actively promotes its relocation to other cellular compartments where they vastly expand its functional repertoire beyond the ER represents a paradigm shift.

This Perspective describes the origin and linkage of GRP78 to the UPR and the mechanisms whereby ER stress actively promotes export of GRP78 from the ER, as exemplified by its translocation to the cell surface where it acts as a multifaceted receptor and a conduit for drug and viral entry, as well as its translocation into the nucleus, where it assumes the surprising role of a transcriptional regulator whereby reprogramming the cell’s transcriptome. Furthermore, this Perspective addresses how these and other atypical localizations of GRP78 impact human disease, with emphasis on cancer and COVID-19, and the exciting prospect that drugs targeting GRP78 could dually suppress tumorigenesis and viral infections.

Web | PDF | Proceedings of the National Academy of Sciences | Open Access

 

[SNT Gatchaman]

A wide range of cancer and viral infections upregulate GRP78 and hijack its functions at multiple locations, thus anti-GRP78 agents can be efficacious against cancer, COVID-19, and other human diseases that depend on stress induction of GRP78 for their pathological progression. Despite these advances, there remain major mysteries and challenges. Regarding mechanisms, most GRP78 expression studies were performed in cell cultures relying on nonphysiological stress inducers; thus, there is a pressing need to advance the field under physiological conditions in vivo. Regarding function, after nearly five decades since its discovery, GRP78 continues to surprise us, as exemplified by the roles of nuclear GRP78 which have yet to be fully explored. The involvement of GRP78 in other pathologies such as neurodegenerative and metabolic diseases not covered in this Perspective is emerging rapidly and deserves vigorous investigations. Finally, drug development on GRP78 is still in its early stages, so the most exciting phase of translation to the clinic has yet to be fulfilled.

 

[SNT Gatchaman]

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (2023) —

WASF3 has been reported to be regulated by BiP (GRP78), an endoplasmic reticulum (ER) chaperone for protein quality control whose defective response can cause ER stress and metabolic disorders. Given the importance of the interaction between the ER and mitochondria for muscle function, we reasoned that ER stress, also reported to play a role in rheumatic diseases which often feature fatigue, may regulate WASF3 in muscle cells. Indeed, the ER stress marker PERK was significantly higher while BiP was lower in the ME/CFS muscle samples. This discordance between PERK and BiP levels in ME/CFS samples suggested impairment of the canonical ER stress pathway, termed “ER Stress Response Failure,” which has been proposed to result in metabolic disorders.