HSPA5 Target Analysis Report Summary
About the Target
HSPA5, also known as 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.
Based on the given context information, here is a comprehensive summary of key viewpoints regarding HSPA5 (also known as GRP78):
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 translocation and its driving force - Information from source 
 YUM70-mediated cell death through inhibition of GRP78 - Information from source 
 Role of HSPA5 and USP22 in UPR signaling and cell death - Information from source 
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