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Heat Shock Protein (HSP90)

I have seen many folks with Long Haul have significant mutations on this enzyme. Lets explore what it is involved in and see if we can learn something....

From Wikepedia:

"Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.

HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum. It plays critical roles in folding proteins in the secretory pathway such as Toll-like receptors and integrins. It has been implicated as an essential immune chaperone to regulate both innate and adaptive immunity.

Well - its already getting interesting........

Now its linked to ferroptosis.......

"Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1-HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis-mediated cancer therapy."[2]

Um, and also to GPX4, how interesting...

"Our study provides evidence for the involvement of HSP90, a ubiquitous heat shock protein, in mediating ferroptosis resistance. Although HSP90 may not bind directly with GPX4, we found that HSP90 participated in the ferroptosis process by regulating the levels of Lamp-2a in the CMA pathway. The heat shock response is an important system for maintaining cellular homeostasis when cells are under stress, such as in the oxidative stress environment during ferroptosis. Activation of the HSF1/HSPB1 pathway by heat shock or overexpression negatively regulated erastin-induced ferroptosis. Likewise, heat shock triggered an iron-dependent cell death pathway in plants characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS, indicative of ferroptosis ."[3]

Degradation of GPX4 by CMA Pathway During Ferroptosis.

Degradation of GPX4 protein is a pivotal event in ferroptosis, which, in turn, promotes ROS and irreversible lipid peroxidation and, consequently, cell death. Since we found that CDDO blocked the degradation of GPX4 in ferroptosis induced by glutamate or erastin, we next investigated the mechanism by which HSP90 regulated the degradation of GPX4 using several protein degradation inhibitors for different types of protein degradation, including proteasome inhibitors (MG-132 and PS-341) and lysosome inhibitors [chloroquine (CQ), NH4Cl, and Baf-A1]. We found that only the lysosome pathway inhibitor CQ, NH4Cl, or Baf-A1 could inhibit both cell death and GPX4 degradation induced by glutamate or erastin.[3]

Here We Have RSL3 Again - Which Binds To The Repressor Site On.......GPX4:)

"We found that induction of ferroptosis by erastin, glutamate, and RSL3 all led to increases in the levels of Lamp-2a in different cell lines, and that the increased levels of Lamp-2a were inhibited by the addition of CDDO . HSP90 has been shown to associate with Lamp-2a at the lysosomal membrane and to regulate the functional dynamics of the Lamp-2a complexes for CMA activation. Consistently, the interaction between HSP90 and Lamp-2a was induced by erastin and reduced by treatment with CDDO, suggesting that erastin may affect the interaction of HSP90 and Lamp-2a (Fig. 7D). HSP90 may also regulate the stability of Lamp-2a, as the treatment of CDDO also reduced the levels of Lamp-2a in control cells"[3]

"Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis."[3]


"Moreover, the carotenoid strongly prevented the increase of NOX-4, hsp70 and hsp90 expressions as well as the phosphorylation of the redox-sensitive p38, JNK and ERK1/2 induced by the oxysterol. The attenuation of 7-KC-induced oxidative stress by lycopene coincided with a normalization of cell growth in human macrophages. Lycopene prevented the arrest in G0/G1 phase of cell cycle induced by the oxysterol and counteracted the increased expression of p53 and p21. Concomitantly, it inhibited 7-KC-induced apoptosis, by limiting caspase-3 activation and the modulatory effects of 7-KC on AKT, Bcl-2, Bcl-xL and Bax. Comparing the effects of lycopene, β-carotene and (5Z)-lycopene on ROS production, cell growth and apoptosis show that lycopene and its isomer were more effective than β-carotene in counteracting the dangerous effects of 7-KC in human macrophages. Our study suggests that lycopene may act as a potential antiatherogenic agent by preventing 7-KC-induced oxidative stress and apoptosis in human macrophages."

CDDO = Bardoxolone-Methyl

"In vitro, 0.025 and 0.05 µM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 µM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model."[5]


[1] Wikepedia

[2] HSPB1 as a novel regulator of ferroptotic cancer cell death. X Sun 1 2, Z Ou , et. al. Oncogene. . 2015 Nov 5;34(45):5617-25. doi: 10.1038/onc.2015.32. Epub 2015 Mar 2. PMID: 25728673. PMCID: PMC4640181. DOI: 10.1038/onc.2015.32

[3] Chaperone-mediated autophagy is involved in the execution of ferroptosis. Zheming Wu, Yang Geng, Info & Affiliations. February 4, 2019. 116 (8) 2996-3005. PNAS Vol. 116 No.8 Biological Sciences.

[4] Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. Paola Palozza a, Rossella Simone et. al. The Jounal Of Nutritional Biochemistry, Volume 21, Issue 1, January 2010, Pages 34-46.

[5] Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo. Zhiying Pang,#1,* Zengxin Jiang, et. al. Drug Des Devel Ther. 2021; 15: 3735–3747. Published online 2021 Sep 4. doi: 10.2147/DDDT.S314767. PMCID: PMC8428116. PMID: 34511883

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