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PERK (Protein kinase RNA-like Endoplasmic Reticulum Kinase) and GRP78 (Glucose-Regulated Protein 78, also known as BiP, Binding Immunoglobulin Protein) are both key players in the Unfolded Protein Response (UPR), a cellular stress response related to the endoplasmic reticulum (ER). Their relationship is integral to maintaining cellular homeostasis, particularly under conditions of ER stress.
GRP78 regulates the activation of PERK by binding to it under non-stress conditions and releasing it during ER stress, thereby initiating a signaling cascade that helps the cell to cope with the stress and restore normal ER function.
GRP78 binds to SARS-CoV-2 Spike Protein, facilitating viral entry into host cells. This interaction might enhance the infectivity of the virus, making it easier for the virus to infect cells that express high levels of GRP78. For this reason, GPR78 has been targeted for drug options.
Fluoride has been found to increase GRP78 levels in all cell types tested so far.
GRP78 is coupled to Gq/11 (Misra et al, 2008) and interacts with the TSH receptor on the ER level (Siffroi-Fernandez et al., 2004).
GRP78 expression is modulated by thyroid hormone.
COVID-19 (A short list of publications - there are many!)
Abedi Dorcheh F, Balmeh N, Hejazi SH, Allahyari Fard N - "Investigation of the mutated antimicrobial peptides to inhibit ACE2, TMPRSS2 and GRP78 receptors of SARS-CoV-2 and angiotensin II type 1 receptor (AT1R) as well as controlling COVID-19 disease" J Biomol Struct Dyn 18:1-24 (2023) doi: 10.1080/07391102.2023.2292307
https://www.tandfonline.com/doi/full/10 ... 23.2292307
Johnson N, Pattinson C, Burgoyne K, Hijazi K, Houssen WE, Milne BF - "SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78" Chembiochem 13:e202300789 (2024). doi: 10.1002/cbic.202300789
https://chemistry-europe.onlinelibrary. ... .202300789
"We have designed and synthesised cyclic peptides based on the loop structure of amino acids 480-488 of the SARS-CoV-2 spike protein S1 domain from the Wuhan and Omicron variants and showed that both peptides bind to GRP78."
Lazou M, Hutton JR, Chakravarty A, Joseph-McCarthy D - "Identification of a druggable site on GRP78 at the GRP78-SARS-CoV-2 interface and virtual screening of compounds to disrupt that interface" J Comput Aided Mol Des 38(1):6 (2024). doi: 10.1007/s10822-023-00546-w.
https://link.springer.com/article/10.10 ... 23-00546-w
Shafiq A, Khalid U, Abdur Rehman U, Abdullah Almuqri E, Muddassir M, Ahmad S, Khan MI, Khan A, Wei DQ - "Structural basis for the mechanism of interaction of SARS-CoV-2 B.1.640.2 variant RBD with the host receptors hACE2 and GRP78" J Biomol Struct Dyn 42(4):2034-2042 (2024). doi: 10.1080/07391102.2023.2220053
https://www.tandfonline.com/doi/full/10 ... 23.2220053
Fluoride (A short list of publications - there are many!)
Deng H, Kuang P, Cui H, Chen L, Luo Q, Fang J, Zuo Z, Deng J, Wang X, Zhao L - "Sodium fluoride (NaF) induces the splenic apoptosis via endoplasmic reticulum (ER) stress pathway in vivo and in vitro" Aging (Albany NY) 8(12):3552-3567 (2016). doi: 10.18632/aging.101150
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270686/
"NaF-caused ER stress was characterized by up-regulating protein expression levels of glucose-regulated protein 78 (BiP) and glucose-regulated protein 94 (GRP94), and by activating unfolded protein response (UPR)."
Li X, Meng L, Wang F, Hu X, Yu Y - "Sodium fluoride induces apoptosis and autophagy via the endoplasmic reticulum stress pathway in MC3T3-E1 osteoblastic cells" Mol Cell Biochem 454(1-2):77-85 (2019). doi: 10.1007/s11010-018-3454-1
"Endoplasmic reticulum (ER) stress induced by NaF activated the unfolded protein response (UPR) and upregulated the expression of the glucose-regulated proteins 94 (GRP94) and 78 (BiP)."
Li J, Zhang Y, Ma L, Zhang KQ, Lei S, Gu HF - "The effect of fluoride on the expression of GRP-78 and caspase-12 in rat ameloblast" Shanghai journal of stomatology 24(1):1-5 (2015)
"Real-time RT-PCR and Western blot showed the expression of GRP-78 and caspase-12 increased while the fluoride concentration increased."
Ma T, Liu W, Jiang D, Zhang G, Zhao X, Zhang Y, Li Z - "Analysis of Toxic Effects of Fluoride on Ovine Follicular Granulosa Cells Using RNA-Seq" Antioxidants (Basel) 13(5):506 (2024). doi: 10.3390/antiox13050506
https://pubmed.ncbi.nlm.nih.gov/38790611/
"Significantly, this study unveiled fluoride's induction of endoplasmic reticulum (ER) stress in cells, triggering a cascade involving the PERK pathway factor ATF4, leading to cell death via DDIT3/CHOP activation and the subsequent upregulation of CHAC1, ATF3, ERO1α, and TRIB3. These findings provide crucial insights into the toxicity of fluoride in ovine, offering a foundation for mitigating fluoride-related losses in the farming industry."
Niu Q, Chen J, Xia T, Li P, Zhou G, Xu C, Zhao Q, Dong L, Zhang S, Wang A - "Excessive ER stress and the resulting autophagic flux dysfunction contribute to fluoride-induced neurotoxicity" Environ Pollut 233:889-899 (2018). doi: 10.1016/j.envpol.2017.09.015
https://www.sciencedirect.com/science/a ... 911732465X
"NaF exposure induced excessive ER stress and associated apoptosis, as manifested by elevated IRE1α, GRP78, cleaved caspase-12 and cleaved-caspase-3, as well as defective autophagy, as shown by increased Beclin1, LC3-II and p62 expression in hippocampus."
Sun F, Li X, Yang C, Lv P, Li G, Xu H - "A role for PERK in the mechanism underlying fluoride-induced bone turnover" Toxicology 325:52-66 (2014) doi: 10.1016/j.tox.2014.07.006
https://www.sciencedirect.com/science/a ... 3X14001395
"A novel finding of this study was that expression of PKR-like endoplasmic reticulum kinase (PERK) was the same trend with receptor activator for nuclear factor-κ B ligand (RANKL), and NF-E2 p45-related factor 2 (Nrf2) was the same trend with Runt-related transcription factor 2 (Runx2) in bones of rats exposed to varied fluoride condition."
Note the dose- and time-dependent effects of various fluoride doses, similar to its activity on many G-protein-coupled receptors.
(NOTE: These are standard doses given to rodents to produce dental fluorosis.)
Wang R, Gong W, Jiang Y, Yin Q, Wang Z, Wu J, Zhang M, Li M, Liu Y, Wang J, Chen Y, Ji Y - "Fluoride exposure during puberty induces testicular impairment via ER Stress-triggered apoptosis in mice" Food Chem Toxicol 114773 (2024). doi: 10.1016/j.fct.2024.114773
https://www.sciencedirect.com/science/a ... 1524003399
"Moreover, qRT-PCR and western blot analyses confirmed the upregulation of both Grp78 mRNA and protein expression, as well as increased mRNA expression of other ER stress-associated genes (Grp94, chop, Atf6, Atf4, and Xbp1) and enhanced protein expression of phosphorylated PERK, IRE1α, eIF2α, JNK, XBP-1, ATF-6α, ATF-4, and CHOP."
Xu H, Zhou YL, Zhang XY, Lu P, Li GS - "Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells" Toxicology 277(1-3):1-5 (2010). doi: 10.1016/j.tox.2010.08.006
https://www.sciencedirect.com/science/a ... 3X10003240
"We found that early and continuous fluoride exposure increased the binding immunoglobulin protein (BiP) expression [GRP78] and activated the PERK signaling pathway, resulting in activation of transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2)."
Yu Y, Xia F, Liu R, Yan Y, Yin L - "Effect of Calcium Supplementation and TMEM16A Inhibition on Endoplasmic Reticulum Stress Induced by Dental Fluorosis in Mice" Discov Med 36(183):753-764 (2024) doi: 10.24976/Discov.Med.202436183.71
https://www.discovmed.com/EN/10.24976/D ... 2436183.71
Jinyi L, Keyu Y, Shanshan D, Shuyang H, Ruirui L, Qingyu G, Fei L - "ERS Mediated by GRP-78/PERK/CHOP Signaling Is Involved in Fluoride-Induced Ameloblast Apoptosis" Biol Trace Elem Res 202(3):1103-1114 (2024). doi: 10.1007/s12011-023-03746-5
https://link.springer.com/article/10.10 ... 23-03746-5
"Excessive fluoride induces apoptosis by activating ERS, which is mediated by GRP-78/PERK/CHOP signaling."
Thyroid
Bektur Aykanat NE, Şahin E, Kaçar S, Bağcı R, Karakaya Ş, Burukoğlu Dönmez D, Şahintürk V -"Investigation of the effect of hyperthyroidism on endoplasmic reticulum stress and tran- sient receptor potential canonical 1 channel in the kidney" Turk J Med Sci 51(3):1554-1563 (2021) doi: 10.3906/sag-2007-109
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283502/
"Immunohistochemical results showed an increase in TRPC1, GRP78, and ATF6 in the hyperthyroid rat (p < 0.05)."
Dos Anjos Cordeiro JM, Santos LC, de Oliveira LS, Santos BR, Santos EO, Barbosa EM, de Macêdo IO, de Freitas GJC, Santos DA, de Lavor MSL, Silva JF - "Maternal hypothyroidism causes oxidative stress and endoplasmic reticulum stress in the maternal-fetal interface of rats" Free Radic Biol Med 191:24-39 (2022) doi: 10.1016/j.freeradbiomed.2022.08.033
https://www.sciencedirect.com/science/a ... 4922005615
"At 18 DG, hypothyroidism increased the placental ROS levels and the decidual and/or placental immunostaining of HIF1α, 8-OHdG, MDA, ATF4, GRP78 and CHOP, while it reduced the immunostaining and enzymatic activity of SOD1, CAT, GST. Hypothyroidism increased the placental mRNA expression of Hifα, Nrf2, Sod2, Gpx1, Cat, Perk, Atf6 and Chop at 18 DG, while decreasing the decidual expression of Sod2, Cat and Atf6. "
Torres-Manzo AP, Franco-Colín M, Blas-Valdivia V, Pineda-Reynoso M, Cano-Europa E - "Hypothyroidism Causes Endoplasmic Reticulum Stress in Adult Rat Hippocampus: A Mechanism Associated with Hippocampal Damage" Oxid Med Cell Longev 2018:2089404 (2018). doi: 10.1155/2018/2089404.
https://pubmed.ncbi.nlm.nih.gov/29743975/
"We conclude that the endoplasmic reticulum stress might play a pivotal role in the activation of hypothyroidism-induced hippocampal cell death."
Wang Q, Ma X, Zhang C - "Effects of thyroid hormone on ovarian cell apoptosis in the rat" Reprod Fertil Dev 32(12):1060-1066 (2020). doi: 10.1071/RD20110
https://pubmed.ncbi.nlm.nih.gov/32758353/
"These results provide evidence that TH dysregulation alters the GRP78 expression profile, triggering the apoptotic signalling pathway, and suggest that GRP78 is a novel mediator of TH in follicle development."
TSH
Siffroi-Fernandez S, Giraud A, Lanet J, Franc JL - "Association of the thyrotropin receptor with calnexin, calreticulin and BiP. Efects on the maturation of the receptor" Eur J Biochem 269(20):4930-7 (2002). doi: 10.1046/j.1432-1033.2002.03192.x.
https://febs.onlinelibrary.wiley.com/do ... 02.03192.x
"BiP [GPR78] increased the degradation of TSHR at the endoplasmic reticulum level. These data suggest that BiP has a negative effect on the folding of TSHR. The interaction of this receptor with BiP leads to an increase in the degradation of TSHR and also to a decrease in the amount of TSHR able to reach the Golgi apparatus, where the complex-type structures are acquired...These results show that calnexin, calreticulin and BiP [GPR78] all interact with TSHR and that the choice made between these two chaperone systems is crucial because each of them has distinct effects on the folding and stability of this receptor at the endoplasmic reticulum level."
Gq/11
Dong DD, Zhou H, Li G -"GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway" BMB Rep 49(11):623-628 (2016). doi: 10.5483/bmbrep.2016.49.11.133
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346323/
Misra UK, Pizzo SV - "Heterotrimeric Galphaq11 co-immunoprecipitates with surface-anchored GRP78 from plasma membranes of alpha2M*-stimulated macrophages" J Cell Biochem 104(1):96-104 (2008) doi: 10.1002/jcb.21607
https://onlinelibrary.wiley.com/doi/10.1002/jcb.21607
"We show here that plasma membrane-associated GRP78 is coupled to pertussis toxin-insensitive Gαq11 and forms a ternary signaling complex with MTJ-1."
ESSENTIAL: Fluoride & Iodine
Liu H, Zeng Q, Cui Y, Zhao L, Zhang L, Fu G, Hou C, Zhang S, Yu L, Jiang C, Wang Z, Chen X, Wang A - "The role of the IRE1 pathway in excessive iodide- and/or fluoride-induced apoptosis in Nthy-ori 3-1 cells in vitro" Toxicol Lett 224(3):341-8 (2014) doi: 10.1016/j.toxlet.2013.11.001
https://www.sciencedirect.com/science/a ... 741301391X
"Elevated expression of binding protein (BiP), IRE1, and C/EBP homologous protein (CHOP) mRNA and protein, as well as spliced X-box-binding protein-1 (sXBP-1) mRNA, were observed in the 1 mM NaF and 50 mM KI +1 mM NaF groups."
Here are the actual findings:
