Human heat shock cognate protein (HSC70/HSPA8) interacts with negatively charged phospholipids by a different mechanism than other HSP70s and brings HSP90 into membranes

Dores-Silva, Paulo R.; Cauvi, David M.; Coto, Amanda L. S.; Silva, Noeli S.M.; Borges, Júlio César; Maio, Antonio De

doi:10.1007/s12192-021-01210-8

Cited by 19 publications

(11 citation statements)

References 66 publications

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“…Interestingly, 0.5 μM concentration of GA effectively alleviated RFP toxicity on HepG2 cells as well as AML12 cells (Figure 4A). Next, we examined the expression of HSP90AA1, HSP90AB1 and HSPA8 in rifampicin‐stimulated cells, since HSPA8 has been described to interact functionally with the Hsp90‐complex 22,23 . However, no significant difference was observed in Hsp90AA1 and AB1 expression among the groups with the extension of RFP exposure in HepG2 cells (Figure 4B).…”

Section: Resultsmentioning

confidence: 96%

“…Next, we examined the expression of HSP90AA1, HSP90AB1 and HSPA8 in rifampicin-stimulated cells, since HSPA8 has been described to interact functionally with the Hsp90-complex. 22,23 However, no significant difference was observed in Hsp90AA1 and AB1 expression among the groups with the extension of RFP exposure in HepG2 cells (Figure 4B). Surprisingly, HSPA8 expression decreased significantly with the prolongation of rifampicin treatment time (Figure 4B).…”

Section: The Hspa8/autophagy Pathway Is Associated With Ferritinophag...mentioning

confidence: 93%

“…2,3 Previous studies showed that INH, RFP and PZA, as well as their metabolites, exhibited substantial direct toxicity against hepatocytes. 4,5 In China, it is estimated that the incidence of anti-TB DILI is about 2.55%(106/4304), 6 which accounts for approximately 21.99% of the total DILI hospitalizations(general was 23.80 per 100 000). 7 Among them, RFP is the most common causative agent for anti-TB DILI.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

Tan

et al. 2022

Liver International

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Background and Aim Rifampicin is the most common pathogenic factor in anti‐tuberculosis drug‐induced liver injury (AT‐DILI), the mechanisms that it promotes hepatocyte damage in AT‐DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity. Methods Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis‐related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention. Results We found that ferritinophagy‐induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high‐throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule‐associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model. Conclusions The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT‐DILI.

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Section: Resultsmentioning

confidence: 96%

Section: The Hspa8/autophagy Pathway Is Associated With Ferritinophag...mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

Tan

et al. 2022

Liver International

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“…The results demonstrated that ame-miR-34 potentially played diverse regulatory roles in the larval guts of A. m. ligustica. In animals and plants, hsp is a critical regulator in maintaining cell homeostasis and protecting cells from various environmental stresses [27][28][29]. Liang et al [30] reported that during infection with brown planthopper hsp derived from southern rice black-streaked dwarf virus (SRBSDV), the viruses not only competed for the host endoplasmic reticulum (ER) and made the membrane protein properly fold or assemble but also promoted viral reproduction.…”

Section: Discussionmentioning

confidence: 99%

ame-miR-34 modulates the larval body weight and immune response ofApis melliferaworkers toAscosphara apisinvasion

Guo

Fan

et al. 2022

Preprint

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MiRNAs are critical regulators of numerous physiological and pathological processes. Ascosphaera apis exclusively infects bee larvae and causes chalkbrood disease. However, the func-tion and mechanism of miRNAs in the bee larval response to A. apis infection is poorly understood. Here, ame-miR-34, a previously predicted miRNA involved in the response of Apis mellifera ligustica larvae to A. apis invasion, was subjected to molecular validation, and overexpression and knockdown were then conducted to explore the regulatory functions of ame-miR-34 in larval body weight and immune response. Stem-loop RT‒PCR and Sanger sequencing confirmed the authen-ticity of ame-miR-34 in the larval gut of A. m. ligustica. RT‒qPCR results demonstrated that com-pared with that in the uninfected larval guts, the expression level of ame-miR-34 was significantly downregulated (P < 0.001) in the guts of A. apis-infected 4-, 5-, and 6-day-old larvae, indicative of the remarkable suppression of host ame-miR-34 due to A. apis infection. In comparison with the corresponding negative control (NC) groups, the expression level of ame-miR-34 in the larval guts in the mimic-miR-34 group was significantly upregulated (P < 0.001), while that in the inhibi-tor-miR-34 group was significantly downregulated (P < 0.01). Similarly, effective overexpression and knockdown of ame-miR-34 were achieved. In addition, the body weights of 5- and 6-day-old larvae were significantly increased compared with those in the mimic-NC group; the weights of 5-day-old larvae in the inhibitor-miR-34 group were significantly decreased in comparison with those in the inhibitor-NC group, while the weights of 4- and 6-day-old larvae in the inhibi-tor-miR-34 group were significantly increased, indicating the involvement of ame-miR-34 in modulating larval body weight. Furthermore, the expression levels of both hsp and abct in the guts of A. apis-infected 4-, 5- and 6-day-old larvae were significantly upregulated after ame-miR-34 overexpression. In contrast, after ame-miR-34 knockdown, the expression levels of the afore-mentioned two key genes in the A. apis-infected 4-, 5- and 6-day-old larval guts were significantly downregulated. Together, the results demonstrated that effective overexpression and knockdown of ame-miR-34 in both noninfected and A. apis-infected A. m. ligustica larval guts could be achieved by the feeding method, and ame-miR-34 exerted a regulatory function in the host immune re-sponse to A. apis invasion through positive regulation of the expression of hsp and abct. Our findings not only provide a valuable reference for the functional investigation of bee larval miRNAs but also reveal the regulatory role of ame-miR-34 in A. mellifera larval weight and im-mune response. Additionally, the results of this study may provide a promising molecular target for the treatment of chalkbrood disease.

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“…This protein plays a role in lipid metabolism [ 41 ]. Hspa8 encodes a member of the heat shock protein 70 family, which interacts with negative charged phospholipids and acts as a membrane chaperone [ 42 ]. These increases might be the result of protective responses to cold-induced stress in BAT [ 43 ], or these HSPs may participate in the BAT metabolism directly, because HSPs are specific molecular chaperones that play various roles in metabolism [ 44 ] as well as protein quality control [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptome Profiling of Young and Old Brown Adipose Tissue Thermogenesis

Kim

Kang

Ryu

et al. 2021

IJMS

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Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty acid. Therefore, the thermogenesis of BAT may be harnessed to treat obesity and related diseases. In mice and humans, BAT levels decrease with aging, and the underlying mechanism is elusive. Here, we compared the transcriptomic profiles of both young and aged BAT in response to thermogenic stimuli. The profiles were extracted from the GEO database. Intriguingly, aging does not cause transcriptional changes in thermogenic genes but upregulates several pathways related to the immune response and downregulates metabolic pathways. Acute severe CE upregulates several pathways related to protein folding. Chronic mild CE upregulates metabolic pathways, especially related to carbohydrate metabolism. Our findings provide a better understanding of the effects of aging and metabolic responses to thermogenic stimuli in BAT at the transcriptome level.

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Human heat shock cognate protein (HSC70/HSPA8) interacts with negatively charged phospholipids by a different mechanism than other HSP70s and brings HSP90 into membranes

Cited by 19 publications

References 66 publications

Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

ame-miR-34 modulates the larval body weight and immune response ofApis melliferaworkers toAscosphara apisinvasion

Comparative Transcriptome Profiling of Young and Old Brown Adipose Tissue Thermogenesis

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