JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-α

Wang, Jianhua; Li, Chuanyu; Liu, Yuelong; Wan, Mei; Yu, Shaohua; Liu, Cunren; Zhang, Liming; Cao, Xu; Kimberly, Robert P.; Grizzle, William E.; Zhang, Huang Ge

doi:10.2353/ajpath.2006.051161

Cited by 23 publications

(18 citation statements)

References 51 publications

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“…This is true particularly for TNFalpha, which does not induce apoptosis in RA-FLS at all but rather promotes proliferation. As demonstrated by the group of John D. Mountz, TNFalpha can induce apoptosis in RA-FLS only, when NFkappaB is inhibited, e.g., by gene transfer of dominant negative IkappaB [25] and recent studies have identified the c-Jun activation domain-binding protein-1 (Jab1) as one further important inhibitor of TNFalpha mediated apoptosis in RA-FLS [24]. While the data for TRAIL have been conflicting [21,23], most recent data suggest that although RA-FLS exhibit an apoptotic response following stimulation with TRAIL, the susceptibility of RA-FLS to TRAIL-induced apoptosis is somewhat lower than to FasL/CD95L and largely depends on the cell cycle (Pundt et al unpublished observation).…”

Section: Ra-fls Are Protected From Receptor-mediated Apoptosis At Mulmentioning

confidence: 97%

“…Although RA-FLS have been demonstrated to express a variety of death inducing surface receptors of the TNFreceptor family such as Fas/CD95 [13], TRAIL-R1 and -R2 [21][22][23] and also TNFR1 [24], multiple lines of evidence indicate that they are relatively resistant also to receptorinduced apoptosis. This is true particularly for TNFalpha, which does not induce apoptosis in RA-FLS at all but rather promotes proliferation.…”

Section: Ra-fls Are Protected From Receptor-mediated Apoptosis At Mulmentioning

confidence: 99%

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Cell death in rheumatoid arthritis

2009

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Apoptosis plays a pivotal role in tissue homoeostasis both under physiological and pathological conditions and several studies have shown that some characteristic changes in the composition and structure of the inflamed synovial membrane in rheumatoid arthritis (RA) are linked to an altered apoptotic response of synovial cells. As a result, a hyperplastic synovial tissue is generated that mediates the progressive destruction of articular cartilage and bone. In addition to inflammatory cells, these changes most prominently affect resident fibroblast-like cells that have been demonstrated to be of utmost importance for joint destruction. Once activated, these cells pass through prominent molecular changes resulting in an aggressive, invasive behaviour. Research of the past years has identified different mechanisms that prevent synovial cells in RA from apoptosis. They include changes in the mitochondrial pathway as well as altered expression of downstream modulators of death receptors and transcriptional regulators such as NFkappaB. This review summarises our recent progress in understanding aberrant apoptosis in the RA synovial membrane and points to possibilities of intervening specifically with this aspect of the pathogenesis of RA.

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Section: Ra-fls Are Protected From Receptor-mediated Apoptosis At Mulmentioning

confidence: 97%

Section: Ra-fls Are Protected From Receptor-mediated Apoptosis At Mulmentioning

confidence: 99%

Cell death in rheumatoid arthritis

2009

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“…This speculation is supported by recent data indicating that CSN5 is dysregulated in both different types of cancers and aging-related diseases. 5,[34][35][36][37][38][39] Although we have identified a role for the CSN5 subunit of COP9 in TLR-mediated innate immune responses of macrophages, further research is needed to understand why KO of CSN5 leads to preferential prevention of activation of p38 and Erk1/2 but not of NF-B in macrophages and also how these activities impinge on the overall physiology of the organism. …”

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confidence: 98%

Plant homologue constitutive photomorphogenesis 9 (COP9) signalosome subunit CSN5 regulates innate immune responses in macrophages

Deng

Pardi

Cheadle

et al. 2011

Blood

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COP9 plays a role in plant innate immunity. The role of COP9 in mammalian innate immune responses is unknown. Here, we show that the COP9 signalosome subunit 5 (CSN5) is required for activation of proinflammatory kinases p38 and Erk and for down-regulation of the expression of genes regulated by nuclear factor E2-related factor 2. Mice with myeloid-specific CSN5 deficiency have lower mortality in polymicrobial sepsis. CSN5 is required for both Toll-like receptor (TLR) and reactive oxygen species-mediated deneddylation of Cul3, which is essential for Cul3/Keap1-mediated degradation of nuclear factor E2-related factor 2. On the basis of our results COP9 subunit CSN5 is considered to be an essential component of mammalian innate immunity. IntroductionPlants, unlike mammals, lack a somatic adaptive immune system. Instead, they rely on innate immunity, and COP9 plays a role in plant innate immune responses. 1,2 The role of COP9 in mammalian innate immune responses is unknown. The COP9 signalosome (CSN) is an evolutionarily conserved multisubunit complex (CSN1-CSN8) that regulates the activity of cullin-RING ubiquitin ligases by removing the ubiquitin-like peptide NEDD8. [3][4][5] Among the 8 subunits of the CSN, CSN5 is the most probable component to play a critical role in holo-CSN complex-dependent deneddylase activity. 6 CSN5 has been implicated in the functions of cytokine macrophage migration inhibitor factor 7 and leukocyte functional antigen 1. 8 Little is known about the inflammatory signaling pathways of TLRs that are regulated by CSN5 in macrophages, a cell type central to the initiation of innate immune responses.TLRs have been shown to play a crucial role in host defense against pathogenic microbes in innate immunity. TLR ligand binding leads to activation of several MAPK pathways that modulate inflammatory responses. The nuclear factor E2-related factor 2 (NRF2) is a master transcriptional activator of genes encoding numerous cytoprotective enzymes that are induced in response to TLR ligand stimuli 9-13 and endogenously derived oxidative/electrophilic agents such as reactive oxygen species (ROS). 14 However, how NRF2 cross talk with proinflammatory pathways occurs on TLR activation has not been established.In this study, we sought to examine the function of CSN5 in innate immune responses by conditional ablation of CSN5 gene expression, specifically in myeloid cells. Knockout (KO) of CSN5 in macrophages significantly attenuates the induction of phosphorylated p38 and Erk on TLR ligand stimulation. The attenuation is specific for MAPK p38 and Erk without affecting activation of NF-B. Depletion of CSN5 in macrophages leads to a marked increase in the regulation of a group of antioxidation and anti-inflammatory genes, including HO-1, which plays a critical role in anti-inflammation. [15][16][17] The up-regulation of HO-1 is correlated with the reduction of Cul3 and enhancement of neddylated Cul3 in macrophages and the accumulation of NRF2. KO of CSN5 also enhanced ROS-mediated neddylation of Cul3. These fi...

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“…A pGEX-CSN5 construct was generated by PCR amplification from the pcDNA3-CSN5 template, 19 using forward primer 5Ј-TTGTTGGGATCCATGGCGGCGTCCGGGAGC-GGTAT-3Ј and reverse primer 5Ј-CTATTAGAATTCTTAA-GAGATGTTAATTTGATT-3Ј (BamHI and EcoRI restriction sites are underlined). The pGEX-CSN5 construct was generated by ligating annealed primers in-frame into BamHI-EcoRI digested pGEX-2T vector (Amersham Biosciences).…”

Section: Csn5 Plasmid Dna Constructsmentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18][19][20] The CSN core is composed of eight subunits (CSN1-8), 20 and associates with different types of proteins including kinases, ligases, and adaptor proteins. CSN is also related structurally and architecturally to the lid subcomplex of the 26S proteasome that mediates degradation of ubiquitin-conjugated proteins.…”

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confidence: 99%

COP9-Associated CSN5 Regulates Exosomal Protein Deubiquitination and Sorting

Liu

Shah

Xiang

et al. 2009

The American Journal of Pathology

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Ubiquitinated endosomal proteins that are deposited into the lumens of multivesicular bodies are either sorted for lysosomal-mediated degradation or secreted as exosomes into the extracellular milieu. The mechanisms that underlie the sorting of cellular cargo proteins are currently unknown. In this study, we show that the COP9 signalosome (CSN)-associated protein CSN5 quantitatively regulated proteins that were sorted into exosomes. Western blot analysis of exosomal proteins indicated that small interfering (si)RNA knockdown of CSN5 results in increased levels of both ubiquitinated and non-ubiquitinated exosomal proteins, including heat shock protein 70, in comparison with exosomes isolated from the supernatants of 293 cells transfected with scrambled siRNA. Furthermore, 293 cells transfected with JAB1/MPN/ Mov34 metalloenzyme domain-deleted CSN5 produced exosomes with higher levels of ubiquitinated heat shock protein 70, which did not affect non-ubiquitinated heat shock protein 70 levels. The loss of COP9-associated deubiquitin activity of CSN5 also led to the enhancement of HIV Gag that was sorted into exosomes as well as the promotion of HIV-1 release, suggesting that COP9-associated CSN5 regulates the sorting of a number of exosomal proteins in both a CSN5 JAB1/MPN/Mov34 metalloenzyme domain-dependent and -independent manner. We propose that COP9-associated CSN5 regulates exosomal protein sorting in both a deubiquitinating activity-dependent and -independent manner, which is contrary to the current idea of ubiquitin-dependent sorting of proteins to exosomes.

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JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-α

Cited by 23 publications

References 51 publications

Cell death in rheumatoid arthritis

Cell death in rheumatoid arthritis

Plant homologue constitutive photomorphogenesis 9 (COP9) signalosome subunit CSN5 regulates innate immune responses in macrophages

COP9-Associated CSN5 Regulates Exosomal Protein Deubiquitination and Sorting

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