E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

Xue, Peng; Liu, Xiaojuan; Shen, Yuntian; Ju, Yuanyuan; Lu, Xiaochun; Zhang, Jinlong; Xu, Guanhua; Sun, Yuyu; Chen, Jiajia; Gu, Haiyan; Cui, Zhiming; Bao, Guofeng

doi:10.1007/s11064-018-2578-8

Cited by 3 publications

(2 citation statements)

References 57 publications

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“…C-Cbl and Cbl-b are two members of Cblfamily E3 ligases that display a high degree of sequence similarity (7). Peripheral nerve injury has been shown to reduce the protein level of C-Cbl in spinal cord microglia, which allows for the microglia activation and subsequent release of proinflammatory factors (15). Our data demonstrated that CFA injection did not influence the total Cbl-b expression in spinal dorsal horn of adult mice.…”

Section: Discussionmentioning

confidence: 57%

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Ubiquitination and functional modification of GluN2B subunit–containing NMDA receptors by Cbl-b in the spinal cord dorsal horn

et al. 2020

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N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund’s adjuvant resulted in the dephosphorylation of Cbl-b at Tyr363, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.

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Section: Discussionmentioning

confidence: 57%

“…2B). As well, C-Cbl, the Cbl-b homology protein that is also present in the spinal cord and is involved in pain processing (15), did not interact with GluN2B (Fig. 2B).…”

Section: Cbl-b Specifically Interacts With Nmdar Subunit Glun2bmentioning

confidence: 92%

Ubiquitination and functional modification of GluN2B subunit–containing NMDA receptors by Cbl-b in the spinal cord dorsal horn

et al. 2020

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HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation

Yeh,

Chang,

Kan

et al. 2023

Mol Neurobiol

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Role of the Ubiquitin System in Chronic Pain

Cheng

Deng

Zhou

2021

Front. Mol. Neurosci.

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As a significant public health issue, chronic pain, mainly neuropathic pain (NP) and inflammatory pain, has a severe impact. The underlying mechanisms of chronic pain are enigmatic at present. The roles of ubiquitin have been demonstrated in various physiological and pathological conditions and underscore its potential as therapeutic targets. The dysfunction of the component of the ubiquitin system that occurs during chronic pain is rapidly being discovered. These results provide insight into potential molecular mechanisms of chronic pain. Chronic pain is regulated by ubiquitination, SUMOylation, ubiquitin ligase, and deubiquitinating enzyme (DUB), etc. Insight into the mechanism of the ubiquitin system regulating chronic pain might contribute to relevant therapeutic targets and the development of novel analgesics.

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E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

Cited by 3 publications

References 57 publications

Ubiquitination and functional modification of GluN2B subunit–containing NMDA receptors by Cbl-b in the spinal cord dorsal horn

Ubiquitination and functional modification of GluN2B subunit–containing NMDA receptors by Cbl-b in the spinal cord dorsal horn

HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation

Role of the Ubiquitin System in Chronic Pain

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