Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-1

Collier-Hyams, Lauren S.; Sloane, Valerie; Batten, Brigid; Neish, Andrew S.

doi:10.4049/jimmunol.175.7.4194

Cited by 112 publications

(107 citation statements)

References 35 publications

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“…Similarly, we show that the ANXA1 mimetic peptide Ac2-26 can inhibit NF-κB in a redox-dependent manner (Supplemental Figure 7). These findings are consistent with our past observations that ROS induced by exogenous agents serves to suppress NF-κB activation by the same biochemical mechanism shown herein: namely, oxidative inactivation of catalytic cysteines in the active site of enzymes involved in processing ubiquitin-like proteins necessary for NF-κB activation (79,80). In the context of wound injury, the ROS-mediated activation of pro-restitution enzymes such as FAK that stimulate epithelial cell migration would be effectively linked and coordinated with blockade of NF-κB and consequent cellular inflammation that would impede optimal wound healing.…”

Section: Figuresupporting

confidence: 82%

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

et al. 2012

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N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1 -/-IEC and AnxA1 -/-mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.

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Section: Figuresupporting

confidence: 82%

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

et al. 2012

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“…One known physiologic effecter of Cul-1 deneddylation is the interaction of non-pathogenic commensal intestinal bacteria and gut epithelial cells [5]. Recent data reveals that this interaction results in the rapid loss neddylated Cul-1 and consequent repression of the NFkB pathway [5; 8].…”

Section: Introductionmentioning

confidence: 99%

“…In detail, NEDD8 must be conjugated to the cullin subunit of the E3-SCG complex on Lys 720 for optimal ubiquitin ligase activity [5; 6]. More importantly, NEDD8 modification of Cul-1 has been demonstrated to be required for the ubiquitination of IKB α and subsequent activation of NF-kB in mammalian cells [5]. In short, Deneddylated Cul-1 is incapable of ubiquitination of IkB α; hence NF-kB cannot become active and initiate the inflammatory response [4; 5].…”

Section: Introductionmentioning

confidence: 99%

Glutamine attenuates inflammation and NF-κB activation via Cullin-1 deneddylation

Singleton

Wischmeyer

2008

Biochemical and Biophysical Research Communications

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Glutamine (GLN) can inhibit NF-kB activation and cytokine expression following sepsis. NF-kB activation and inflammatory cytokine expression, depend on neddylation of Cullin-1 (Cul-1) to proceed. Our aim was to evaluate whether GLN inhibits Cul-1 neddylation, and further determine if GLN-mediated Cul-1 deneddylation attenuates NF-kB activation and subsequent cytokine expression following experimental sepsis in the mouse. Sepsis induced via cecal-liagtion and puncture (CLP) led to a significant increase in lung Cul-1 neddylation. GLN administration postsepsis led to enhanced lung Cul-1 deneddylation and attenuated NEDD8 expression (p< 0.01 vs. saline). Cul-1 deneddylation was associated with decreased NF-kB activation and IKBα degradation in GLN treated mice (*p < 0.01 vs. saline). Lastly, GLN treatment led to a significant decrease in lung TNF-α and IL-6 post-sepsis. These are the first data describing a direct effect of GLN on Cul-1 deneddylation and provide a possible mechanistic explanation for GLN's antiinflammatory effects.

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“…A major band between 90 and 100 kDA is usually recognized as neddylated Cullins (Nedd8-Cullin) and was examined in the present study (22)(23)(24)(25)(26)(27). As predicted, the major band was detected in the neutrophils, and MLN4924 treatment for 30 min led to diminished Nedd8-Cullin in a dose-dependent manner (Fig.…”

Section: Cells (D) Nkt Cells and (E) B Cells (F) The Purity Of Gr1+mentioning

confidence: 79%

MLN4924 suppresses lipopolysaccharide‑induced proinflammatory cytokine production in neutrophils in a dose‑dependent manner

Jin

Jing²,

Ye³

et al. 2018

Oncol Lett

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Abstract. Neddylation is a ubiquitination-like pathway. It has been reported that neddylation inhibition with the pharmacological agent MLN4924 potently uppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, by preventing the degradation of phosphorylated inhibitor of κB (p-IκB) in macrophages. However, whether neddylation serves a similar role in neutrophils remains unknown. In the present study MLN4924 treatment led to the accumulation of P-IκBα in neutrophils as well as the decreased production of TNF-α, IL-6 and IL-1β in response to LPS, in a dose-dependent manner. The viability of neutrophils was only marginally affected in the same conditions, without statistical significance. Furthermore, the nuclear factor (NF)-κB inhibitor JSH-23 mimicked the effects of MLN4924 in neutrophils, and the inhibitory effects of MLN4924 on LPS-induced proinflammatory cytokine production diminished in the presence of JSH-23. Thus, the results of the present study suggest that neddylation inhibition suppresses neutrophil function by suppressing the NF-κB signaling pathway. IntroductionNeutrophils serve crucial roles in the anti-bacterial and anti-fungal innate immune response and produce cytokines to initiate inflammatory responses; however, their inappropriate or excessive activation contributes to tissue damage during autoimmune and inflammatory diseases (1). Furthermore, the activity of neutrophils is associated with tumor progression, as demonstrated in colitis-associated cancer and glioblastoma (2,3).Previous studies have revealed that in order to protect the human body from invading pathogens and endogenous damage-associated molecules, neutrophils sense these threats through innate immune receptors, such as toll-like receptors (TLRs) and other pattern recognition receptors, to upregulate the secretion of inflammatory cytokines (4,5). The recognition of lipopolysaccharide (LPS) from gram-negative bacteria by TLR4 is a well-characterized example with the initiation of proinflammatory gene transcription through multiple signaling pathways, including nuclear factor (NF)-κB) (6,7). The exposure of neutrophils to bacterial LPS may contribute to tissue damage, under certain conditions, including endotoxic shock and infection-induced adult respiratory distress syndrome (8).Neddylation is a novel-type protein post-translational modification, a multistep enzymatic process that adds the ubiquitin-like molecule neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) to target proteins in an ATP-dependent manner. Neddylation is vital for a range of processes, including cell viability, growth and development (9-12). To the best of our knowledge, the only known E1 for neddylation is a heterodimer comprised of the amyloid precursor protein-binding protein and ubiquitin-like modifier activating enzyme 3 (9-12). A previous study identified the ubiquitin-conjugating enzymes Ube2M and Ube2F as Nedd8 E2s (13). Several targets for N...

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Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-1

Cited by 112 publications

References 35 publications

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

Glutamine attenuates inflammation and NF-κB activation via Cullin-1 deneddylation

MLN4924 suppresses lipopolysaccharide‑induced proinflammatory cytokine production in neutrophils in a dose‑dependent manner

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