Geranylgeranylacetone, an Inducer of the 70-kDa Heat Shock Protein (HSP70), Elicits Unfolded Protein Response and Coordinates Cellular Fate Independently of HSP70

Endo, Satoshi; Hiramatsu, Naoki; Hayakawa, Kunihiro; Okamura, Maro; Kasai, Ayumi; Tagawa, Yasuhiro; Sawada, Norifumi; Yao, Jian; Kitamura, Masanori

doi:10.1124/mol.107.039164

Cited by 40 publications

(33 citation statements)

References 41 publications

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“…The rat mesangial cell line SM43 and stable transfectants (SM/Neo, SM/ NFB-SEAP, SM/GRP78) were established as described previously (25)(26)(27). SM/NFB-SEAP cells produce secreted alkaline phosphatase (SEAP) under the control of the NF-B enhancer elements (26).…”

Section: Cells and Stable Transfectantsmentioning

confidence: 99%

Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation

Hayakawa

Hiramatsu

Okamura

et al. 2009

The Journal of Immunology

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Acute endoplasmic reticulum (ER) stress causes induction of inflammatory molecules via activation of NF-κB. However, we found that, under ER stress conditions, renal mesangial cells acquire anergy to proinflammatory stimuli. Priming of the cells with ER stress inducers (tunicamycin, thapsigargin, A23187, and AB5 subtilase cytotoxin) caused blunted induction of MCP-1 in response to TNF-α, IL-1β, macrophage-derived factors, or bystander macrophages. The magnitude of suppression was closely correlated with the level of GRP78, an endogenous indicator of ER stress. The suppression of MCP-1 under ER stress conditions was reversible and observed in general regardless of cell types or triggers of ER stress. The decrease in the level of MCP-1 mRNA was ascribed to transcriptional suppression via unexpected inhibition of NF-κB, but not to accelerated mRNA degradation. Subsequent experiments revealed that TNFR-associated factor 2, an essential component for TNF-α signaling, was down-regulated by ER stress. We also found that, under ER stress conditions, expression of NF-κB suppressor A20 was induced. Overexpression of A20 resulted in suppression of cytokine-triggered NF-κB activation and knockdown of A20 by RNA interference significantly attenuated induction of anergy by ER stress. In contrast, other ER stress-inducible/-related molecules that may suppress NF-κB (e.g., GRP78, NO, reactive oxygen species, and IκB) were not involved in the inhibitory effects of ER stress. These results elucidated ER stress-dependent mechanisms by which nonimmune cells acquire anergy to inflammatory stimuli under pathological situations. This self-defense machinery may play a role in halting progression of acute inflammation and in its spontaneous subsidence.

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Section: Cells and Stable Transfectantsmentioning

confidence: 99%

Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation

Hayakawa

Hiramatsu

Okamura

et al. 2009

The Journal of Immunology

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“…We previously reported that treatment of SM43 mesangial cells with thapsigargin caused activation of the ATF6 and the IRE1 pathways. 13 To confirm that the PERK-eIF2␣ pathway is also activated by ER stress, we treated mesangial cells with thapsigargin and tested induction of ATF4, the indicator of UPR downstream of PERK and eIF2␣. Northern blot analysis revealed that ATF4 was substantially induced by the treatment with thapsigargin ( Figure 4A).…”

Section: Involvement Of C/ebp␤ In the Suppression Of Nf-b By Er Stressmentioning

confidence: 99%

“…To confirm this result, we used mesangial cells stably expressing a dominant negative mutant of XBP1. 13 We treated mock-transfected SM/Neo cells and SM/XBP1-DN cells with thapsigargin and subjected them to Northern blot analysis. The result showed that dominant negative inhibition of XBP1 did not attenuate ER stress-triggered induction of C/EBP␤ (data not shown), confirming the lack of involvement of the XBP1 pathway.…”

Section: Involvement Of C/ebp␤ In the Suppression Of Nf-b By Er Stressmentioning

confidence: 99%

ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ

Hayakawa

Nakajima

Hiramatsu

et al. 2010

Journal of the American Society of Nephrology

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Modest induction of endoplasmic reticulum (ER) stress confers resistance to inflammation in glomeruli. Recently, we found that ER stress leads to mesangial insensitivity to cytokine-induced activation of NF-B, but the underlying mechanisms are incompletely understood. ER stress can trigger expression of CCAAT/enhancer-binding proteins (C/EBPs), which interact with transcription factors including NF-B. Here, we investigated a role for C/EBPs in the ER stress-induced resistance to cytokines. Mesangial cells preferentially induced C/EBP␤ after exposure to thapsigargin or tunicamycin; induction of C/EBP␦ was modest and transient, and expression of C/EBP␣ was absent. The induction of C/EBP␤ correlated with accumulation of C/EBP␤ protein and enhanced transcriptional activity of C/EBP. Overexpression of C/EBP␤ markedly suppressed TNF-␣-induced activation of NF-B, independent of its transacting potential. Knockdown of C/EBP␤ by small interfering RNA reversed the suppressive effect of ER stress on NF-B. In vivo, preconditioning of mice with ER stress induced renal C/EBP␤ and suppressed NF-Bdependent gene expression in response to LPS. Using dominant negative mutants and null mutants for individual branches of the unfolded protein response, we identified the RNA-dependent protein kinaselike ER kinase (PERK) and the inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) pathways as the unfolded protein response responsible for ER stress-induced C/EBP␤. These results suggest that ER stress blunts cytokine-triggered activation of NF-B, in part through PERK-and IRE1-mediated preferential induction of C/EBP␤.

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“…Geranylgeranylacetone (GGA) is a widely-used HSP70 inducer; however, recently it was shown that GGA could also elicit UPR [52,53]. Oral uptake of GGA attenuates ARHL in mice [54].…”

Section: Er Stress and Age-related Hearing Lossmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Hearing Loss

Wang

2017

JOHBM

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Abstract:The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.

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Geranylgeranylacetone, an Inducer of the 70-kDa Heat Shock Protein (HSP70), Elicits Unfolded Protein Response and Coordinates Cellular Fate Independently of HSP70

Cited by 40 publications

References 41 publications

Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation

Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation

ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ

Endoplasmic Reticulum Stress in Hearing Loss

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