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

Deng, Zhongbin; Pardi, Ruggero; Cheadle, William G.; Xiang, Xiaoyu; Zhang, Shuangyin; Shah, Spandan V.; Grizzle, William E.; Miller, Donald R.; Mountz, John D.; Zhang, Huang Ge

doi:10.1182/blood-2010-10-314526

Cited by 21 publications

(25 citation statements)

References 39 publications

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“…With respect to CSN5, the clearness of the identified antiatherogenic (and antiinflammatory) effects is remarkable, as previous studies have also linked CSN5 to proinflammatory JNK/ AP1 signaling and proatherogenic LFA-1 integrin activation while counteracting inflammatory MIF activity (14)(15)(16). This may be the result of COP9 complex-associated vs. complexindependent activities.…”

Section: /Apoementioning

confidence: 89%

“…CSN5 is the only CSN subunit with catalytic activity and acts as part of the holocomplex and independently of the CSN (11). Importantly, CSN5 has also been linked to inflammatory regulation (14)(15)(16). Whereas the conjugation of NEDD8 to cullins, termed NEDDylation, is required for an optimal ubiquitin ligase activity of the SCFs (17)(18)(19)(20), CSN-mediated deNEDDylation has been linked with the dissociation of the substrate-binding module from the SCF complex and with inhibition of SCF-mediated substrate ubiquitination in vitro (21,22).…”

Section: Significancementioning

confidence: 99%

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Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

Asare

Ommer-Bläsius

Azombo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed "deNEDDylase") and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloidspecific Csn5 deletion. Genetic deletion of Csn5 in Apoe −/− mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.A therosclerosis is the primary cause of cardiovascular diseases. As a chronic inflammatory condition of the vessel wall, atherosclerosis is characterized by endothelial cell activation resulting in the secretion of chemoattractant proteins such as CCL2 and macrophage migration inhibitory factor (MIF) and by increased expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These molecules synergize to sequentially recruit inflammatory cells such as monocytes and T lymphocytes into the vessel wall (1-3).The transcription factor NF-κB plays a crucial role in vascular inflammation and atherogenesis, e.g., by controlling the expression of inflammatory cytokines, chemokines, and adhesion molecules that orchestrate the recruitment and adhesion of leukocytes. Also, numerous genes that regulate differentiation, survival, and proliferation of vascular and immune cells involved in the inflammatory response are targets of NF-κB (4). In resting cells, the NF-κB dimer, p65 and p50, is inactivated by binding to the inhibitor of κB (IκB)-α protein. Inflammatory challenges such as LPS or TNF-α exposure trigg...

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Section: /Apoementioning

confidence: 89%

Section: Significancementioning

confidence: 99%

Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

Asare

Ommer-Bläsius

Azombo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, it has been reported that lipopolysaccharide-induced shock and polymicrobial sepsis induces early and greater mortality in Nrf2-deficent mice, which is related to the lethal innate immune response [44]. In contrast, transgenic mice with a decreased rate of Nrf2 degradation showed lower mortality in polymicrobial sepsis [45]. Consequences of the down-regulation of the Nrf2 host difference mechanism still remain to be fully explored.…”

Section: The Chain Of Redox Eventsmentioning

confidence: 99%

Bench-to-bedside review: Sepsis - from the redox point of view

et al. 2011

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The pathogenesis of sepsis and its progression to multiple organ dysfunction syndrome and septic shock have been the subject of investigations for nearly half a century. Controversies still exist with regard to understanding the molecular pathophysiology of sepsis in relation to the complex roles played by reactive oxygen species, nitric oxide, complements and cytokines. In the present review we categorise the key turning points in sepsis development and outline the most probable sequence of events leading to cellular dysfunction and organ failure under septic conditions. We have applied an integrative approach in order to fuse current state-of-the-art knowledge about redox processes involving hydrogen peroxide, nitric oxide, superoxide, peroxynitrite and hydroxyl radical, which lead to mitochondrial respiratory dysfunction. Finally, from this point of view, the potential of redox therapy targeting sepsis is discussed.

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“…Furthermore, Jab1 overexpression has been implicated in the initiation and progression of various cancers, suggesting an oncogenic role (Shackleford and Claret, 2010). The constitutive deletion of Jab1 in mice results in early embryonic lethality by E8.5 with impaired proliferation and accelerated apoptosis (Tomoda et al, 2004;Tian et al, 2010), whereas cell typespecific deletions of Jab1 in T-cell, B-cell, or myeloid cells all lead to severe postnatal cell differentiation defects and increased apoptosis (Panattoni et al, 2008;Deng et al, 2011;Sitte et al, 2012). Thus, Jab1 plays essential roles both in general embryogenesis and in the differentiation of specific organs and tissues.…”

Section: Introductionmentioning

confidence: 99%

The transcriptional co-regulator Jab1 is crucial for chondrocyte differentiation in vivo

Chen

Bashur

Liang

et al. 2013

Journal of Cell Science

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SummaryThe evolutionarily conserved transcriptional cofactor Jab1 plays critical roles in cell differentiation, proliferation, and apoptosis by modulating the activity of diverse factors and regulating the output of various signaling pathways. Although Jab1 can interact with the bone morphogenetic protein (BMP) downstream effector Smad5 to repress BMP signaling in vitro, the role of Jab1 in BMP-mediated skeletogenesis in vivo is still poorly understood. As a key regulator of skeletogenesis, BMP signaling regulates the critical Ihh-Pthrp feedback loop to promote chondrocyte hypertrophy. In this study, we utilized the loxP/Cre system to delineate the specific role of Jab1 in cartilage formation. Strikingly, Jab1 chondrocyte-specific knockout Jab1 flox/flox ; Col2a1-Cre (cKO) mutants exhibited neonatal lethal chondrodysplasia with severe dwarfism. In the mutant embryos, all the skeletal elements developed via endochondral ossification were extremely small with severely disorganized chondrocyte columns. Jab1 cKO chondrocytes exhibited increased apoptosis, G2 phase cell cycle arrest, and increased expression of hypertrophic chondrocyte markers Col10a1 and Runx2. Jab1 can also inhibit the transcriptional activity of Runx2, a key regulator of chondrocyte hypertrophy. Notably, our study reveals that Jab1 is likely a novel inhibitor of BMP signaling in chondrocytes in vivo. In Jab1 cKO chondrocytes, there was heightened expression of BMP signaling components including Gdf10/Bmp3b and of BMP targets during chondrocyte hypertrophy such as Ihh. Furthermore, Jab1 cKO chondrocytes exhibited an enhanced response to exogenous BMP treatment. Together, our study demonstrates that Jab1 represses chondrocyte hypertrophy in vivo, likely in part by downregulating BMP signaling and Runx2 activity.

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

Cited by 21 publications

References 39 publications

Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

Bench-to-bedside review: Sepsis - from the redox point of view

The transcriptional co-regulator Jab1 is crucial for chondrocyte differentiation in vivo

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