PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1

Wang, Lin; Zhou, Yunting; Chen, Zijuan; Sun, Lei; Wu, Juehui; Li, Haohao; Liu, Feng; Wang, Fei; Yang, Chunfu; Yang, Juhao; Leng, Qibin; Zhang, Qingli; Xu, Ajing; Shen, Lisong; Sun, Jinqiao; Wu, Dianqing; Fang, Changming; Lu, Haojie; Yan, Dapeng; Ge, Baoxue

doi:10.1038/s41467-019-08524-3

Cited by 22 publications

(17 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, except that viruses inhibited positive regulators, such as β-arrestin 2, to achieve immune evasion in the present study, some other viruses also use the opposite strategy that enhances the expression of negative regulators to eventually evade the host immune response. For example, one of our previous studies demonstrated that virus-induced PLCβ2 negatively regulates virus-induced proinflammatory responses by inhibiting the activation of TAK1 48 . However, while the devil climbs a post, the priest climbs ten.…”

Section: Discussionmentioning

confidence: 99%

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Zhang

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

show abstract

Section: Discussionmentioning

confidence: 99%

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Zhang

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…PLCβ2 knockout mice are more resistant to infections by viruses. Viral infections cause uncontrolled release of proinflammatory cytokines through activation of the MAPKKK, TAK1 (TGFβ-activated kinase 1) [186]. TAK1 interacts with PLCβ2 as well as with PI(4,5)P 2 .…”

Section: Plcβ2mentioning

confidence: 99%

Phospholipase C families: Common themes and versatility in physiology and pathology

Katan

Cockcroft

2020

Progress in Lipid Research

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

“…Thus, it would be interesting to test whether DAG production or [Ca 2+ ] i itself contributes to the restoration of tLTP and contextual fear memory impairment. Methodologically, although we directly injected m-3M3FBS into the dorsal and ventral hippocampi of 5XFAD mice, other studies administered m-3M3FBS via intraperitoneal injections [ 93 , 94 ]. To enhance the therapeutic effectiveness in neurological disorders, it remains to be determined whether oral administration or intraperitoneal injection of m-3M3FBS can pass the blood-brain barrier to activate PLCβ directly.…”

Section: Discussionmentioning

confidence: 99%

Activation of PLCβ1 enhances endocannabinoid mobilization to restore hippocampal spike-timing-dependent potentiation and contextual fear memory impaired by Alzheimer’s amyloidosis

Lee

Kwag

2021

Alz Res Therapy

View full text Add to dashboard Cite

Background Accumulation of amyloid beta oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal long-term potentiation (LTP), leading to memory deficits. Thus, identifying the molecular targets of AβO involved in LTP inhibition is critical for developing therapeutics for AD. Endocannabinoid (eCB) synthesis and release, a process collectively called eCB mobilization by hippocampal CA1 pyramidal cells, is known to facilitate LTP induction. eCB can be mobilized either by postsynaptic depolarization in an intracellular Ca2+ concentration ([Ca2+]i)-dependent pathway or by group 1 metabotropic glutamate receptor (mGluR) activation in a phospholipase Cβ (PLCβ)-dependent pathway. Moreover, group 1 mGluR activation during postsynaptic depolarization, which is likely to occur in vivo during memory processing, can cause synergistic enhancement of eCB (S-eCB) mobilization in a PLCβ-dependent pathway. Although AβO has been shown to disrupt [Ca2+]i-dependent eCB mobilization, the effect of AβO on PLCβ-dependent S-eCB mobilization and its association with LTP and hippocampus-dependent memory impairments in AD is unknown. Methods We used in vitro whole-cell patch-clamp recordings and western blot analyses to investigate the effect of AβO on PLCβ protein levels, PLCβ-dependent S-eCB mobilization, and spike-timing-dependent potentiation (tLTP) in AβO-treated rat hippocampal slices in vitro. In addition, we assessed the relationship between PLCβ protein levels and hippocampus-dependent memory impairment by performing a contextual fear memory task in vivo in the 5XFAD mouse model of AD. Results We found that AβO treatment in rat hippocampal slices in vitro decreased hippocampal PLCβ1 protein levels and disrupted S-eCB mobilization, as measured by western blot analysis and in vitro whole-cell patch-clamp recordings. This consequently led to the impairment of NMDA receptor (NMDAR)-mediated tLTP at CA3-CA1 excitatory synapses in AβO-treated rat hippocampal slices in vitro. Application of the PLCβ activator, m-3M3FBS, in rat hippocampal slices reinstated PLCβ1 protein levels to fully restore S-eCB mobilization and NMDAR-mediated tLTP. In addition, direct hippocampal injection of m-3M3FBS in 5XFAD mice reinstated PLCβ1 protein levels to those observed in wild type control mice and fully restored hippocampus-dependent contextual fear memory in vivo in 5XFAD mice. Conclusion We suggest that these results might be the consequence of memory impairment in AD by disrupting S-eCB mobilization. Therefore, we propose that PLCβ-dependent S-eCB mobilization could provide a new therapeutic strategy for treating memory deficits in AD.

show abstract

PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1

Cited by 22 publications

References 48 publications

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Phospholipase C families: Common themes and versatility in physiology and pathology

Activation of PLCβ1 enhances endocannabinoid mobilization to restore hippocampal spike-timing-dependent potentiation and contextual fear memory impaired by Alzheimer’s amyloidosis

Contact Info

Product

Resources

About