HSPA5

HSPA5, also known as BiP (Binding immunoglobulin Protein) or GRP78 (glucose-regulated protein 78), is a gene that encodes a member of the heat shock protein 70 (HSP70) chaperone family. The encoded protein is an endoplasmic reticulum (ER) luminal chaperone that assists in the folding and assembly of newly synthesized polypeptides and helps maintain ER homeostasis.

BiP functions as a molecular chaperone by recognizing exposed hydrophobic regions in unfolding or misfolded proteins and using ATP-dependent cycles to bind and release substrates. It is central to ER quality control and the unfolded protein response, coordinating protein folding with ER-associated degradation when folding capacity is overwhelmed. BiP also participates in translocation of polypeptides into the ER and collaborates with other ER chaperones, such as calnexin and calreticulin, in the maturation of glycoproteins. The protein is retained in the ER through a C-terminal KDEL sequence, which retrieves it from the Golgi back to the ER.

HSPA5 expression is tightly regulated by ER stress through the unfolded protein response, involving the transcription factors ATF6, IRE1, and PERK. Upregulation of BiP increases the ER’s capacity to manageMisfolded proteins during stress.

Clinically, BiP/GRP78 is widely used as a marker of ER stress and is linked to various diseases. It is frequently upregulated in cancer, where it can support tumor cell survival and therapy resistance, and it has been implicated in neurodegenerative diseases and metabolic disorders.