Fbxo3-dependent fbxl2 ubiquitination mediates neuropathic allodynia through the TRAF2/TNIK/GluR1 cascade

Tzer Bin Lin, Ming Chun Hsieh, Cheng Yuan Lai, Jen Kun Cheng, Yat Pang Chau, Ting Ruan, Gin Den Chen, Hsien Yu Peng

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK-GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylation-associated GluR1 trafficking. Although exhibiting no effect on Fbxo3/Fbxl2/TRAF2 signaling, focal knockdown of spinal TNIK expression prevented SNL-induced allodynia by attenuating TNIK/GluR1 phosphorylation-dependent subcellular GluR1 redistribution. In contrast, intrathecal administration of BC-1215 (N1,N2-Bis[[4-(2-pyridinyl)phenyl]methyl]-1,2-ethanediamine) (a novel Fbxo3 inhibitor) pre-vented SNL-induced Fbxl2 ubiquitination and subsequent TFAF2 de-ubiquitination to ameliorate behavioral allodynia via antagonizing TRAF2/TNIK/GluR1 signaling. By targeting spinal Fbxo3-dependent Fbxl2 ubiquitination and the subsequent TRAF2/TNIK/GluR1 cas-cade, spinal application of a TNF-÷-neutralizing antibody ameliorated SNL-induced allodynia, and, conversely, intrathecal TNF-÷ injection into naive rats induced allodynia via a spinal Fbxo3/Fbxl2-dependent modification of the TRAF2/TNIK/GluR1 cascade. To-gether, our results suggest that spinal TNF-÷ contributes to the development of neuropathic pain by upregulating TRAF2/TNIK/GluR1 signaling via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic pain by targeting the F-box protein or TNIK.

Original languageEnglish
Pages (from-to)16545-16560
Number of pages16
JournalJournal of Neuroscience
Volume35
Issue number50
DOIs
Publication statusPublished - Dec 16 2015

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
F-Box Proteins
Ubiquitination
Hyperalgesia
Neuralgia
Posterior Horn Cells
ethylenediamine
Neuronal Plasticity
Phosphorylation
Phosphotransferases
Juniperus
Spinal Injections
Spinal Nerves
Neutralizing Antibodies
Ligation
Analgesics
Cell Membrane
Therapeutics

Keywords

  • Fbxl2
  • Fbxo3
  • GluR1
  • Neuropathic
  • TNIK
  • Ubiquitination

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Fbxo3-dependent fbxl2 ubiquitination mediates neuropathic allodynia through the TRAF2/TNIK/GluR1 cascade. / Lin, Tzer Bin; Hsieh, Ming Chun; Lai, Cheng Yuan; Cheng, Jen Kun; Chau, Yat Pang; Ruan, Ting; Chen, Gin Den; Peng, Hsien Yu.

In: Journal of Neuroscience, Vol. 35, No. 50, 16.12.2015, p. 16545-16560.

Research output: Contribution to journalArticle

Lin, Tzer Bin ; Hsieh, Ming Chun ; Lai, Cheng Yuan ; Cheng, Jen Kun ; Chau, Yat Pang ; Ruan, Ting ; Chen, Gin Den ; Peng, Hsien Yu. / Fbxo3-dependent fbxl2 ubiquitination mediates neuropathic allodynia through the TRAF2/TNIK/GluR1 cascade. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 50. pp. 16545-16560.
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abstract = "Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK-GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylation-associated GluR1 trafficking. Although exhibiting no effect on Fbxo3/Fbxl2/TRAF2 signaling, focal knockdown of spinal TNIK expression prevented SNL-induced allodynia by attenuating TNIK/GluR1 phosphorylation-dependent subcellular GluR1 redistribution. In contrast, intrathecal administration of BC-1215 (N1,N2-Bis[[4-(2-pyridinyl)phenyl]methyl]-1,2-ethanediamine) (a novel Fbxo3 inhibitor) pre-vented SNL-induced Fbxl2 ubiquitination and subsequent TFAF2 de-ubiquitination to ameliorate behavioral allodynia via antagonizing TRAF2/TNIK/GluR1 signaling. By targeting spinal Fbxo3-dependent Fbxl2 ubiquitination and the subsequent TRAF2/TNIK/GluR1 cas-cade, spinal application of a TNF-÷-neutralizing antibody ameliorated SNL-induced allodynia, and, conversely, intrathecal TNF-÷ injection into naive rats induced allodynia via a spinal Fbxo3/Fbxl2-dependent modification of the TRAF2/TNIK/GluR1 cascade. To-gether, our results suggest that spinal TNF-÷ contributes to the development of neuropathic pain by upregulating TRAF2/TNIK/GluR1 signaling via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic pain by targeting the F-box protein or TNIK.",
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T1 - Fbxo3-dependent fbxl2 ubiquitination mediates neuropathic allodynia through the TRAF2/TNIK/GluR1 cascade

AU - Lin, Tzer Bin

AU - Hsieh, Ming Chun

AU - Lai, Cheng Yuan

AU - Cheng, Jen Kun

AU - Chau, Yat Pang

AU - Ruan, Ting

AU - Chen, Gin Den

AU - Peng, Hsien Yu

PY - 2015/12/16

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N2 - Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK-GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylation-associated GluR1 trafficking. Although exhibiting no effect on Fbxo3/Fbxl2/TRAF2 signaling, focal knockdown of spinal TNIK expression prevented SNL-induced allodynia by attenuating TNIK/GluR1 phosphorylation-dependent subcellular GluR1 redistribution. In contrast, intrathecal administration of BC-1215 (N1,N2-Bis[[4-(2-pyridinyl)phenyl]methyl]-1,2-ethanediamine) (a novel Fbxo3 inhibitor) pre-vented SNL-induced Fbxl2 ubiquitination and subsequent TFAF2 de-ubiquitination to ameliorate behavioral allodynia via antagonizing TRAF2/TNIK/GluR1 signaling. By targeting spinal Fbxo3-dependent Fbxl2 ubiquitination and the subsequent TRAF2/TNIK/GluR1 cas-cade, spinal application of a TNF-÷-neutralizing antibody ameliorated SNL-induced allodynia, and, conversely, intrathecal TNF-÷ injection into naive rats induced allodynia via a spinal Fbxo3/Fbxl2-dependent modification of the TRAF2/TNIK/GluR1 cascade. To-gether, our results suggest that spinal TNF-÷ contributes to the development of neuropathic pain by upregulating TRAF2/TNIK/GluR1 signaling via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic pain by targeting the F-box protein or TNIK.

AB - Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK-GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylation-associated GluR1 trafficking. Although exhibiting no effect on Fbxo3/Fbxl2/TRAF2 signaling, focal knockdown of spinal TNIK expression prevented SNL-induced allodynia by attenuating TNIK/GluR1 phosphorylation-dependent subcellular GluR1 redistribution. In contrast, intrathecal administration of BC-1215 (N1,N2-Bis[[4-(2-pyridinyl)phenyl]methyl]-1,2-ethanediamine) (a novel Fbxo3 inhibitor) pre-vented SNL-induced Fbxl2 ubiquitination and subsequent TFAF2 de-ubiquitination to ameliorate behavioral allodynia via antagonizing TRAF2/TNIK/GluR1 signaling. By targeting spinal Fbxo3-dependent Fbxl2 ubiquitination and the subsequent TRAF2/TNIK/GluR1 cas-cade, spinal application of a TNF-÷-neutralizing antibody ameliorated SNL-induced allodynia, and, conversely, intrathecal TNF-÷ injection into naive rats induced allodynia via a spinal Fbxo3/Fbxl2-dependent modification of the TRAF2/TNIK/GluR1 cascade. To-gether, our results suggest that spinal TNF-÷ contributes to the development of neuropathic pain by upregulating TRAF2/TNIK/GluR1 signaling via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic pain by targeting the F-box protein or TNIK.

KW - Fbxl2

KW - Fbxo3

KW - GluR1

KW - Neuropathic

KW - TNIK

KW - Ubiquitination

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