HSP90 is required for TAK1 stability but not for its activation in the pro‐inflammatory signaling pathway

Liu, Xin Yu; Seh, Cheah Chen; Cheung, Pierina

doi:10.1016/j.febslet.2008.10.053

Cited by 14 publications

(19 citation statements)

References 26 publications

(38 reference statements)

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“…Interestingly, our results indicate that a one-hour treatment with 17-AAG results in the complete insolubility of IRAK-1 while only a fraction of TAK1 is insoluble under these conditions. Our data showing partial insolubility of TAK1 is consistent with the work by Liu et al (26) that reported that Hsp90 binding to TAK1 is required for its folding and stability, but is released when TAK1 binds to TAB1. Thus, the soluble fraction of TAK1 likely represents a stable form of TAK1 that does not form a protein complex with Hsp90.…”

Section: Discussionsupporting

confidence: 93%

Activation of the Heat Shock Response Attenuates the Interleukin 1β–Mediated Inhibition of the Amiloride-Sensitive Alveolar Epithelial Ion Transport

Howard

Roux²,

Iles³

et al. 2013

Shock

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Acute lung injury (ALI) is a clinical syndrome characterized by hypoxia which is caused by the breakdown of the alveolar capillary barrier. IL-1β a cytokine released within the airspace in ALI, down-regulates αENaC transcription and protein expression via p38 MAP kinase-dependent signaling. While induction of the heat shock response can restore alveolar fluid clearance compromised by IL-1β following the onset of severe hemorrhagic shock in rats, the mechanisms are not fully understood. In this study, we report that the induction of the heat shock response prevents IL-1β-dependent inhibition of αENaC mRNA expression and subsequent channel function. Heat shock results in IRAK1 detergent insolubility and a disruption of Hsp90 binding to IRAK1. Likewise, TAK1, another client protein of Hsp90 and signaling component of the IL-1β pathway is also detergent insoluble after heat shock. Twenty-four hours post-heat shock, both IRAK1 and TAK1 are again detergent soluble, which correlates with the IL-1β-dependent p38 activation. Remarkably, IL-1β-dependent p38 activation 24-hour post-heat shock did not result in an inhibition of αENaC mRNA expression and channel function. Further analysis demonstrates prolonged preservation of αENaC expression by the activation of the heat shock response that involves inducible Hsp70. Inhibition of Hsp70 at 24 hours post-heat shock results in p38-dependent IL-1β inhibition of αENaC mRNA expression while over-expression of Hsp70 attenuates the p38-dependent IL-1β inhibition of αENaC mRNA expression. These studies demonstrate new mechanisms by which the induction of the heat shock response protects the barrier function of the alveolar epithelium in acute lung injury.

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Section: Discussionsupporting

confidence: 93%

Activation of the Heat Shock Response Attenuates the Interleukin 1β–Mediated Inhibition of the Amiloride-Sensitive Alveolar Epithelial Ion Transport

Howard

Roux²,

Iles³

et al. 2013

Shock

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“…Interestingly, we found that the expression of TAK1 was decreased along with the increase of HSP70 and vise versa (Figure 2). It has been previously reported that HSP90 regulates IL-1β-induced signaling by interacting with TAK1 [26] and HSP90 is required for the folding and stability of TAK1 [30]. We thus further determined the impact of inducible HSP70 on the complex of HSP90-TAK1 in HeLa cells.…”

Section: Resultsmentioning

confidence: 92%

Inducible HSP70 Antagonizes IL-1β Cytocidal Effects through Inhibiting NF-kB Activation via Destabilizing TAK1 in HeLa Cells

et al. 2012

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BackgroundDespite several reports describing the HSP70-mediated cytoprotection against IL-1, the precise mechanism for this phenomenon remains to be determined.Methods/Principal FindingsHere we used HeLa cells, a human epithelial carcinoma cell line, to evaluate the role of inducible HSP70 in response of IL-1β stimulation. We found that inducible HSP70 antagonized the cytotoxicity of IL-1β and improved the survival of HeLa cells. Further investigation demonstrated that increased expression level of inducible HSP70 reduced the complex of TAK1 and HSP90, and promoted the degradation of TAK1 protein via proteasome pathway. By overexpression and RNAi knockdown, we showed that inducible HSP70 modulated the NF-kB but not MAPKs signalings through influencing the stability of TAK1 protein in HeLa cells. Moreover, overexpression of HSP70 attenuated the production of iNOS upon IL-1β stimulation, validating that inducible HSP70 serves as a cytopretective factor to antagonize the cytocidal effects of IL-1β in HeLa cells.Conclusions/SignificanceOur observations provide evidence for a novel signaling mechanism involving HSP70, TAK1, and NF-κB in the response of IL-1β cytocidal effects. This research also provides insight into mechanisms by which HSP70 exerts its cytoprotective action upon toxic stimuli in tumor cells.

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“…MKK4 is a direct substrate of TAK1, thus it is possible TAK1 also associates with Filamin A to stimulate MKK4/JNK signaling. Additionally, TAK1 is known to be a client of HSP90 (43). TAK1-mediated phosphorylation of a close relative, endoplasmin (HSP90B1), suggests TAK1 is capable of interacting with additional heatshock proteins.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPaseactivating protein (GAP) enzymes, and is exclusive to membranelocalized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

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HSP90 is required for TAK1 stability but not for its activation in the pro‐inflammatory signaling pathway

Cited by 14 publications

References 26 publications

Activation of the Heat Shock Response Attenuates the Interleukin 1β–Mediated Inhibition of the Amiloride-Sensitive Alveolar Epithelial Ion Transport

Activation of the Heat Shock Response Attenuates the Interleukin 1β–Mediated Inhibition of the Amiloride-Sensitive Alveolar Epithelial Ion Transport

Inducible HSP70 Antagonizes IL-1β Cytocidal Effects through Inhibiting NF-kB Activation via Destabilizing TAK1 in HeLa Cells

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

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