TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

Zhang, Dingding; Huang, Yan; Li, Hua; Hao, Shuangying; Zhuang, Zong; Liu, Ming; Sun, Qing; Yang, Yiqing; Zhou, Meifang; Li, Kuanyu; Hang, Chun-Hua

doi:10.1074/jbc.m115.636795

Cited by 44 publications

(47 citation statements)

References 46 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with the data from a previous study, the level of total TAK1 kept constant after SAH and p-TAK1 increased significantly after SAH, indicating that TAK1 was activated post SAH (Fig. 3a ) 34 . While ST2825 treatment significantly reduced the levels of p-TAK1.…”

Section: Resultssupporting

confidence: 91%

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

Huang

Zhang

Wei

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Accumulating of evidence suggests that activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking pro-inflammatory and pro-apoptotic signaling. Myeloid differentiation primary response protein 88 (MyD88) is an endogenous adaptor protein in the toll-like receptors (TLRs) and interleukin (IL) -1β family signaling pathways and acts as a bottle neck in the NF-κB and MAPK pathways. Here, we used ST2825, a selective inhibitor of MyD88, to clarify whether inhibiting MyD88 could provide neuroprotection in EBI following SAH. Our results showed that the expression of MyD88 was markedly increased at 24 h post SAH. Intracerebroventricular injection of ST2825 significantly reduced the expression of MyD88 at 24 h post SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that ST2825 inhibited SAH-induced phosphorylation of TAK1, p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Further, ST2825 administration diminished the SAH-induced inflammatory response and apoptosis. As a result, SAH-induced EBI was alleviated and neurological deficits caused by SAH were reversed. Our findings suggest that MyD88 inhibition confers marked neuroprotection against EBI following SAH. Therefore, MyD88 might be a promising new molecular target for the treatment of SAH.

show abstract

Section: Resultssupporting

confidence: 91%

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

Huang

Zhang

Wei

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Together with the role TAK1 plays in the MAPK pathway, it is also well documented as important in mediating NF‐κB activity in various cell types including HeLa, HEK293T, ex vivo neurons, microglia cells, and B and T lymphocytes, to name a few 24 , 45 48–52 ; however, the precise nature of the TAK1 role has been a challenge to dissect at times. In B cell receptor (BCR) signaling, based on differential knockout models, the kinase activity of TAK1 was shown to be dispensable on the one hand, 45 while others later demonstrated that the physical protein, likely via its interactions 53 (e.g., TAB2 and TAB3) were critical 52 .…”

Section: Discussionmentioning

confidence: 99%

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Watson

Maguire

Rouillard

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro‐inflammatory mediators in response to environmental cues detected by the IgE‐FcεRI complex. The role of TGF‐β‐activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE‐mediated activation under SCF‐c‐kit potentiation in a mast cell‐driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z‐7‐oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell‐mediated responses using IgE‐sensitized murine bone marrow‐derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF‐κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro‐inflammatory cytokines TNF, IL‐6, IL‐13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1‐inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF‐κB pathways in driving the late‐phase response, but also initiation of the degranulation mechanism of the mast cell early‐phase response following allergen recognition and may warrant consideration in future therapeutic development.

show abstract

“…It was phosphorylated in satellite cells upon skeletal muscle injury induced by barium chloride and promoted myofiber regeneration . TAK‐1 was also activated in brain injury following experimental subarachnoid hemorrhage or trauma, and its inhibition reduced downstream signaling and neurologic deficits .…”

Section: Discussionmentioning

confidence: 99%

Rapid Activation of Transforming Growth Factor β–Activated Kinase 1 in Chondrocytes by Phosphorylation and K⁶³‐Linked Polyubiquitination Upon Injury to Animal Articular Cartilage

Ismail

Didangelos

Vincent

et al. 2017

Arthritis & Rheumatology

View full text Add to dashboard Cite

ObjectiveMechanical injury to cartilage predisposes to osteoarthritis (OA). Wounding of the articular cartilage surface causes rapid activation of MAP kinases and NF‐κB, mimicking the response to inflammatory cytokines. This study was undertaken to identify the upstream signaling mechanisms involved.MethodsCartilage was injured by dissecting it from the articular surface of porcine metacarpophalangeal (MCP) joints or by avulsing murine proximal femoral epiphyses. Protein phosphorylation was assayed by Western blotting of cartilage lysates. Immunolocalization of phosphorylated activating transcription factor 2 (ATF‐2) and NF‐κB/p65 was detected by confocal microscopy. Messenger RNA (mRNA) was measured by quantitative reverse transcriptase–polymerase chain reaction (qRT‐PCR). Receptor associated protein 80 (RAP‐80) ubiquitin interacting motif agarose was used in a pull‐down assay to obtain K63‐polyubiquitinated proteins. Ubiquitin linkages on immunoprecipitated transforming growth factor β–activated kinase 1 (TAK‐1) were analyzed with deubiquitinases.ResultsSharp injury to porcine cartilage caused rapid activation of JNK and NF‐κB pathways and the upstream kinases MKK‐4, IKK, and TAK‐1. Pharmacologic inhibition of TAK‐1 in porcine cartilage abolished JNK and NF‐κB activation and reduced the injury‐dependent inflammatory gene response. High molecular weight species of phosphorylated TAK‐1 were induced by injury, indicating its ubiquitination. An overall increase in K63‐linked polyubiquitination was detected upon injury, and TAK‐1 was specifically linked to K63‐ but not K48‐polyubiquitin chains. In mice, avulsion of wild‐type femoral epiphyses caused similar intracellular signaling that was reduced in cartilage‐specific TAK‐1–null mice. Epiphyseal cartilage of MyD88‐null and TRAF‐6–null mice responded to injury, suggesting the involvement of a ubiquitin E3 ligase other than TRAF‐6.ConclusionActivation of TAK‐1 by phosphorylation and K63‐linked polyubiquitination by injury indicates its role in driving cell activation. Further studies are needed to identify the upstream ubiquitination mechanisms, including the E3 ligase involved.

show abstract

TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

Cited by 44 publications

References 46 publications

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Rapid Activation of Transforming Growth Factor β–Activated Kinase 1 in Chondrocytes by Phosphorylation and K⁶³‐Linked Polyubiquitination Upon Injury to Animal Articular Cartilage

Contact Info

Product

Resources

About

TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

Cited by 44 publications

References 46 publications

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Rapid Activation of Transforming Growth Factor β–Activated Kinase 1 in Chondrocytes by Phosphorylation and K63‐Linked Polyubiquitination Upon Injury to Animal Articular Cartilage

Contact Info

Product

Resources

About

Rapid Activation of Transforming Growth Factor β–Activated Kinase 1 in Chondrocytes by Phosphorylation and K⁶³‐Linked Polyubiquitination Upon Injury to Animal Articular Cartilage