HSPA5, GRP78 or BiP, is a crucial protein involved in various cellular processes

NCBI ID: G3309

HSPA5

HSPA5, GRP78 or BiP, is a crucial protein involved in various cellular processes

It is primarily found in the endoplasmic reticulum (ER) where it plays a role in the activation of the unfolded protein response (UPR), ER-associated degradation (ERAD), and regulation of the mitochondria-associated ER membrane (MAM).

GRP78 can be regulated at different levels, including transcriptional regulation mediated by various transcription factors binding to specific motifs in its gene promoter. Additionally, alternative processing of GRP78's pre-mRNA can occur under stressful conditions, resulting in the production of a truncated protein that is retained in the cytosol. Post-transcriptional regulation of GRP78 also occurs through the action of factors on its IRES motif or the action of different miRNAs.

In response to ER conditions, GRP78's activity can be modulated by the protein HYPE, which AMPylates or deAMPylates GRP78 depending on the unfolded protein load in the ER. AMPylated GRP78 is non-functional and pooled into a reservoir, while deAMPylated GRP78 can be activated and function as a chaperone under stress conditions. This switch between AMPylation and deAMPylation states is mediated by specific residues and the interaction with Arg374 and a water molecule.

Furthermore, GRP78 interacts with misfolded proteins, as shown through its interaction with misfolded antitrypsin with the UPR sensor IRE1alpha. This interaction leads to the release of BiP from UPR sensors and subsequent activation of UPR signaling pathways. Misfolded proteins can also induce conformational changes in UPR sensors, such as IRE1alpha and PERK, which activate their kinase and RNase activities. ATF6alpha complexes may undergo disassembly in response to misfolded proteins, migrating to the Golgi for proteolytic processing.

In a different context, GRP78 is implicated in carfilzomib-induced cardiotoxicity, with metformin shown to have a prophylactic effect. In aged myocardium, the induction of autophagy is recognized as a cardioprotective strategy. The combined effect of carfilzomib and metformin resulted in the synergistic induction of autophagy, leading to improved left ventricular function and establishing metformin as a potential prophylactic therapy in aged individuals.

Finally, GRP78's involvement in the canonical Wnt signaling pathway has been investigated. It was found that GRP78 interacts with DCD at the cell surface, regulating cell migration by activating the canonical Wnt signaling pathway. This interaction leads to the activation of beta-catenin transcriptional activity and increased expression of Wnt target genes. The proposed model suggests that GRP78 and DCD interaction influences cell migration and the Wnt signaling pathway.

Overall, GRP78 (HSPA5/BiP) is a multifunctional protein involved in UPR, ERAD, MAM regulation, autophagy induction, and Wnt signaling pathway activation. Its regulation occurs at different levels, including transcriptional and post-transcriptional regulation. Its interaction with HYPE, misfolded proteins, and DCD contributes to its diverse functions within the cell.

HSPA5 is involved in protein translocation into the endoplasmic reticulum (ER) and the mitochondrial matrix.

HSPA5 acts as a driving force for polypeptide insertion into the ER lumen, facilitating the translocation process.

In the ER, HSPA5 binds to nascent polypeptide chains, increasing their entropy as they move away from the membrane constraints.

Allosteric inhibition of HSPA5's activity by YUM70 leads to increased endoplasmic reticulum (ER) stress and prolonged ER stress-mediated apoptosis in pancreatic cancer cells.

HSPA5 is stabilized by USP22, which enhances the protein folding capacity in the ER and maintains low levels of unfolded protein response (UPR) signaling in cancer cells.

Impaired expression of USP22 leads to decreased HSPA5 protein stability, resulting in the accumulation of unfolded proteins in the ER and stimulation of UPR signaling.

Activation of the PERK/ATF4/ATF3 axis in response to UPR induction leads to programmed cell death in a p53-independent manner.

Inhibitors targeting HSPA5, such as HA15, and the PERK activator CCT020312 have been developed and may contribute to the development of new UPR-based anti-cancer therapeutic strategies.

Impaired expression of USP22 sensitizes HER2+-BC (HER2-positive breast cancer) to programmed cell death along the HSPA5/PERK/ATF4/ATF3-axis of the UPR.

Protein Name: Heat Shock Protein Family A (Hsp70) Member 5

Functions: Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166)

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