Classical NF-κB Activation Negatively Regulates Noncanonical NF-κB-dependent CXCL12 Expression

Madge, Lisa A.; May, Michael J.

doi:10.1074/jbc.m110.147207

Cited by 45 publications

(41 citation statements)

References 43 publications

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“…Surprisingly, TNF completely inhibited LIGHT-induced CXCL12 and significantly reduced basal CXCL12 expression in EC. 2 Earlier reports demonstrated that proinflammatory cytokines repress basal CXCL12 expression 3,4 and our findings further establish that classical NFκB signaling blocks the NC NFκB-driven upregulation of CXCL12. Furthermore, when classical NFκB activation was selectively inhibited, TNF-induced expression of classical NFκB-dependent genes was ablated whereas the repression of CXCL12 was reversed and CXCL12 was robustly expressed.…”

supporting

confidence: 64%

The NFκB paradox: RelB induces and inhibits gene expression

Madge¹,

May²

2011

Cell Cycle

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supporting

confidence: 64%

The NFκB paradox: RelB induces and inhibits gene expression

Madge¹,

May²

2011

Cell Cycle

Self Cite

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“…We recently reported that cultured human umbilical vein ECs treated with high-titer PRA from sensitized transplant candidates selectively activated noncanonical but not canonical NF-κB signaling in a mechanism requiring formation of MACs (2). We compared noncanonical NF-κB activation by PRA with LIGHT, a cytokine activator of this pathway (12,13). As expected, LIGHT caused a gradual increase in NIK (Fig.…”

Section: Resultsmentioning

confidence: 99%

Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt ⁺ NIK ⁺ signalosome on Rab5 ⁺ endosomes

Jane‐wit

Surovtseva

Qin

et al. 2015

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

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Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-κB-inducing kinase (NIK) and activating noncanonical NF-κB signaling. Here we report a novel endosome-based signaling complex induced by MACs to stabilize NIK. We found that, in contrast to cytokine-mediated activation, NIK stabilization by MACs did not involve cIAP2 or TRAF3. Informed by a genome-wide siRNA screen, instead this response required internalization of MACs in a clathrin-, AP2-, and dynamin-dependent manner into Rab5 + endosomes, which recruited activated Akt, stabilized NIK, and led to phosphorylation of IκB kinase (IKK)-α. Active Rab5 was required for recruitment of activated Akt to MAC + endosomes, but not for MAC internalization or for Akt activation. Consistent with these in vitro observations, MAC internalization occurred in human coronary ECs in vivo and was similarly required for NIK stabilization and EC activation. We conclude that MACs activate noncanonical NF-κB by forming a novel AktT he complement system contributes to both host defense and immunopathology (1). Using serum with high-titer panel reactive antibody (PRA) from sensitized transplant candidates as a source of complement-fixing human anti-HLA alloantibodies, we identified noncanonical NF-κB signaling as a novel effector pathway used by complement membrane attack complexes (MACs) to induce proinflammatory changes in endothelial cells (ECs) that resulted in increased recruitment and activation of alloreactive effector memory T cells (2).Noncanonical NF-κB signaling is generally initiated by ligand engagement of TNF receptor (TNFR) superfamily members (3, 4). In the absence of ligand, NF-κB-inducing kinase (NIK) protein is persistently translated and sequestered into a complex containing cIAP1, cIAP2, TRAF2, and TRAF3, where it is polyubiquitinylated by cIAP2 and targeted for proteasomal degradation (5). Following ligand activation, TRAF3 along with its associated proteins are recruited to the cytoplasmic tail of the activated receptor (5-7), where the ubiquitin ligase activity of cIAP2 is diverted away from NIK to TRAF3 (8), causing degradation of TRAF3 accompanied by release and stabilization of NIK, which initiates signaling. In this sequence, TRAF3 degradation is necessary and sufficient for NIK accumulation (9, 10). In contrast to canonical NF-κB activation by TNF-α or IL-1, which occurs rapidly within 15 min, noncanonical signaling typically requires ∼8 h for initial detection (11). Here we demonstrate that MAC stabilization of NIK occurs within 30 min independent of the cIAP2-TRAF3-containing signalosome, and that furthermore, an endosome-based Akt-and Rab5-dependent signaling mechanism mediates NIK stabilization by MACs. ResultsStabilization of NIK by MACs Occurs Rapidly and Independently of cIAP2-TRAF3 Signalosome Formation. We recently reported that cultured human umbilical vein ECs treated with high-titer PRA from sensitized transplant candidates selectively activated noncanonical but not canonical NF...

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“…Interestingly, CXCL13 is also regulated in an opposite way by TNF and IL-4 in monocytes and macrophages even if in this case TNF acts as an inducer and IL-4 as a repressor. 54 In addition, TNF-induced classical nuclear factor kB signaling was already shown to inhibit CXCL12 expression in human umbilical vein endothelial cells 55,56 and in a BM stromal cell line. 52,53 The demonstration that TNF/LT-primed stromal cells became more For personal use only.…”

Section: Cd21lmentioning

confidence: 99%

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

Pandey

Mourcin

Marchand

et al. 2017

Blood

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Key Points• FL-infiltrating stromal cells overexpress CXCL12, which triggers FL B-cell migration, adhesion, and activation. Finally, CXCL12 triggered primary FL B-cell activation, migration, and adhesion, a process antagonized by BTK and PI3K inhibitors. These data identified the IL-4/CXCL12 loop as a previously unrecognized pathway involved in lymphoid stroma polarization and as a potential therapeutic target in

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Classical NF-κB Activation Negatively Regulates Noncanonical NF-κB-dependent CXCL12 Expression

Cited by 45 publications

References 43 publications

The NFκB paradox: RelB induces and inhibits gene expression

The NFκB paradox: RelB induces and inhibits gene expression

Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt ⁺ NIK ⁺ signalosome on Rab5 ⁺ endosomes

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

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Classical NF-κB Activation Negatively Regulates Noncanonical NF-κB-dependent CXCL12 Expression

Cited by 45 publications

References 43 publications

The NFκB paradox: RelB induces and inhibits gene expression

The NFκB paradox: RelB induces and inhibits gene expression

Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt + NIK + signalosome on Rab5 + endosomes

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

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Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt ⁺ NIK ⁺ signalosome on Rab5 ⁺ endosomes