Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch

Meng, Qingcai; Cai, Chunmei; Sun, Tingzhe; Wang, Qianliang; Xie, Weidong; Wang, Rongfu; Cui, Jun

doi:10.1083/jcb.201505091

Cited by 48 publications

(53 citation statements)

References 47 publications

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“…But Meng et al. showed that USP14 negatively regulates NF‐кB signaling by removing the polyubiquitin chains from NLRC5 to enhance NLRC5‐mediated inhibition of NF‐κB activation . We discovered that USP14 suppressed VSV‐induced RIG‐I activation through deubiquitinating K63‐linked RIG‐I.…”

Section: Discussionmentioning

confidence: 82%

USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

Zhao

Jing

et al. 2018

Eur J Immunol

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Retinoic acid-inducible gene I (RIG-I) is a critical RNA virus sensor that initiates antiviral immune response through K63-linked ubiquitination. In this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63-linked RIG-I. USP14 knockdown significantly enhanced RIG-I-triggered type I IFN signaling and inhibited vesicular stomatitis virus (VSV) replication both in mouse peritoneal macrophages and THP1 cells. USP14 overexpression in HeLa cells attenuated RIG-I-triggered IFN-β expression and promoted VSV replication. Besides, USP14-specific inhibitor, IU1, increased RIG-I-mediated type I IFN production and antiviral responses in vitro and in vivo. In addition, USP14 could interact with RIG-I and removeRIG-I K63-linked polyubiquitination chains. This article is the first to report that USP14 acts as a negative regulator in antiviral response through deubiquitinating K63-linked RIG-I. These findings provide insights into a potential new therapy targeting USP14 for RNA virus-related diseases.Keywords: Deubiquitination r RIG-I-like receptors r RNA virus sensor r USP14 r Vesicular stomatitis virus (VSV) Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Discussionmentioning

confidence: 82%

USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

Zhao

Jing

et al. 2018

Eur J Immunol

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“…Furthermore, Meng's research found that ubiquitination editing of NLRC5 determined NLRC5-IKKβ interaction dynamics and enhanced the activation of NF-κB signaling [27]. Protein ubiquitination is an exceptionally flexible posttranslational modification which regulates a wide variety of signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…USP14 is one of three proteasome-associated deubiquitinating enzymes that remove ubiquitin from proteasomal substrates prior to their degradation [31]. USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance the interaction between NLRC5 and IKK-β, thus inhibiting NF-κB activation in an NLRC5-dependent coherent feedforward loop (CFL) manner [27]. Given that NLRC5 is involved in many biological processes and functions as a negative regulator of NF-κB and PI3K/Akt signaling pathways, we hypothesized that NLRC5 negatively regulates the titanium particles-induced osteolysis in vitro and in vivo, which is enhanced by USP14.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, TNF-α were observed highly expressed while NLRC5 and USP14 expression decreased in synovial membrane around the prosthesis in the aseptic loosening patients. NLRC5 expression decreased due to the robust ubiquitination upon Ti stimulation, similar to the effect of LPS challenge [27].To further explore how NLRC5 and USP14 function in aseptic loosening, we carry out the following in vitro studies. As described before, titanium particles ranging from 0.2μm to 1.2μm were proved to induced more secretion of proinflammatory cytokine thus were chosen in this study to stimulate the maximal biological effect [29].…”

Section: Discussionmentioning

confidence: 99%

“…Besides, knockdown of NLRC5 in vitro attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway [26]. Recently, it's been reported that Ubiquitin-specific protease 14(USP14) specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5-mediated inhibition of NF-κB signaling [27]. USP14 is one of three proteasome-associated deubiquitinating enzymes that remove ubiquitin from proteasomal substrates prior to their degradation.…”

Section: Introductionmentioning

confidence: 99%

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The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

Fang¹,

Fu²,

et al. 2020

Journal of Biological Chemistry

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Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

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CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

et al. 2016

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Major histocompatibility complex (MHC) class I and class II molecules play essential roles in the development and activation of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator) has been recognized as a master regulator of MHC class II gene expression, albeit knowledge about the regulatory mechanism of MHC class I gene expression had been limited. Recently identified MHC class I transactivator (CITA), or NLRC5, also belongs to the NLR protein family and constitutes a critical regulator for the transcriptional activation of MHC class I genes. In addition to MHC class I genes, CITA/NLRC5 induces the expression of β2 -microglobulin, TAP1 and LMP2, essential components of the MHC class I antigen presentation pathway. Therefore, CITA/NLRC5 and CIITA are transcriptional regulators that orchestrate the concerted expression of critical components in the MHC class I and class II pathways, respectively. © 2016 BioFactors, 42(4):349-357, 2016.

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Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch

Cited by 48 publications

References 47 publications

USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

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