TNFα-induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2

Kim, Joo-Young; Morgan, Michael J.; Kim, Dong‐Gun; Lee, Ju‐Yeon; Bai, Lan; Lin, Yong; Liu, Zheng-gang; Kim, You‐Sun

doi:10.1242/jcs.075770

Cited by 48 publications

(43 citation statements)

References 57 publications

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“…In the latter study, activation of RIP1 was shown to render it a target for caspase 8, generating RIP1 fragments that inhibited IRF3 signaling (23). Our data raise the possibility that inhibitory actions of RIP1 may extend to both the IRF3-and NF-B-dependent components of signaling responses to poly(I·C) through mechanisms as yet uncharacterized but potentially involving potentiation of signaling via noncanonical NF-B (13).…”

Section: Figmentioning

confidence: 59%

“…While these data indicate that RIP1 lies within the pathways regulating responses to poly(I·C) in primary airway epithelial cells, it does not identify the point in the signaling pathways that is regulated by Pellino-1. Although RIP1 is usually thought to be involved in activation of NF-B signaling via interaction with the TRIF signaling pathway (5,17) and IKK complex (13), we note that RIP1 has also been shown very recently to negatively regulate activation of noncanonical NF-B by TNF-␣ signaling (13) and also to negatively regulate the IFR3 induction downstream of RIG-I activation (23). In the latter study, activation of RIP1 was shown to render it a target for caspase 8, generating RIP1 fragments that inhibited IRF3 signaling (23).…”

Section: Figmentioning

confidence: 85%

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Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus

Bennett

Prince

Parker

et al. 2012

J Virol

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Pellino-1 has recently been identified as a regulator of interleukin-1 (IL-1) signaling, but its roles in regulation of responses of human cells to human pathogens are unknown. We investigated the potential roles of Pellino-1 in the airways. We show for the first time that Pellino-1 regulates responses to a human pathogen, rhinovirus minor group serotype 1B (RV-1B). Knockdown of Pellino-1 by small interfering RNA (siRNA) was associated with impaired production of innate immune cytokines such as CXCL8 from human primary bronchial epithelial cells in response to RV-1B, without impairment in production of antiviral interferons (IFN), and without loss of control of viral replication. Pellino-1 actions were likely to be independent of interleukin-1 receptor-associated kinase-1 (IRAK-1) regulation, since Pellino-1 knockdown in primary epithelial cells did not alter responses to IL-1 but did inhibit responses to poly(I·C), a Toll-like receptor 3 (TLR3) activator that does not signal via IRAK-1 to engender a response. These data indicate that Pellino-1 represents a novel target that regulates responses of human airways to human viral pathogens, independently of IRAK signaling. Neutralization of Pellino-1 may therefore provide opportunities to inhibit potentially harmful neutrophilic inflammation of the airways induced by respiratory viruses, without loss of control of the underlying viral infection.

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Section: Figmentioning

confidence: 59%

Section: Figmentioning

confidence: 85%

Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus

Bennett

Prince

Parker

et al. 2012

J Virol

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“…It also is possible that hematopoietic RIPK1 deficiency stimulates the degradation of prosurvival proteins cIAP1/2 and TRAF2, thereby making cell death more likely. In addition to mediating survival, the IAPs have been shown to regulate TNF production; thus RIPK1 deficiency may promote cell death and induce inflammation via effects on cIAP1/2 protein stability (40)(41)(42). Increased chemokine and cytokine production also are features associated with the rapid HSPC death observed in the RosaCreER…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis

Roderick

Hermance

Zelic

et al. 2014

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

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Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is recruited to the TNF receptor 1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. RIPK1 deficiency results in postnatal lethality, but precisely why Ripk1 −/− mice die remains unclear. To identify the lineages and cell types that depend on RIPK1 for survival, we generated conditional Ripk1 mice. Tamoxifen administration to adult RosaCreER T2 Ripk1fl/fl mice results in lethality caused by cell death in the intestinal and hematopoietic lineages. Similarly, Ripk1 deletion in cells of the hematopoietic lineage stimulates proinflammatory cytokine and chemokine production and hematopoietic cell death, resulting in bone marrow failure. The cell death reflected cell-intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, because Ripk3−/− progenitors remain TNF sensitive in vitro and fail to repopulate irradiated mice. These genetic studies reveal that hematopoietic RIPK1 deficiency triggers both apoptotic and necroptotic death that is partially prevented by RIPK3 deficiency. Therefore, RIPK1 regulates hematopoiesis and prevents inflammation by suppressing RIPK3 activation.tumor necrosis factor | programmed necrosis | hematopoietic failure T he proinflammatory cytokine TNF stimulates receptorinteracting serine/threonine-protein kinase 1 (RIPK1) ubiquitination, NFκB and MAPK activation, and induction of apoptosis or necroptosis (1, 2). TNF signaling via TNF receptor 1 (TNFR1) is highly regulated and results in the recruitment of several adapter proteins including TNFR1-associated death domain (TRADD) protein, the E3 ubiquitin ligases cellular inhibitor of apoptosis protein-1 and -2 (cIAP1/2), and TNFRassociated factor 2 (TRAF2) or 5, and the serine threonine death domain-containing kinase RIPK1 (complex I) (1). We have demonstrated that the kinase activity of RIPK1 is not required for NFκB activation (3); rather, RIPK1 is modified by the addition of Lys63-linked and linear polyubiquitin chains (3-6). Polyubiquitinated RIPK1 then recruits NEMO/IκB kinase-γ (IKKγ) to mediate IKK activation and TAK1/TAB2/3 to mediate MAPK activation, resulting in antiapoptotic and proinflammatory gene expression (7,8). Deubiquitination of RIPK1 by cylindromatosis (CYLD) results in the formation of a cytosolic complex containing TRADD, Fas-associated death domain protein (FADD), caspase-8, and RIPK1 (complex IIa) (2). Caspase-8 cleaves and inactivates RIPK1 and CYLD and stimulates apoptosis (9-11). In the absence of caspase-8 or the presence of caspase inhibitors, TNF family members and potentially other ligands stimulate the kinase activity of RIPK1 to induce necroptosis (9, 11-16). RIPK1 also is recruited to the Toll-like receptor adapter TRIF via the Rip homotypic interaction motif (RHIM) to mediate NFκB activation (17) and, under conditions of caspase-8 inhibition, initiates necroptosis (14, 16). Necrostatin-1 (Nec-1), an allosteric RIPK1 inhibitor, inhibits necroptosis induced by TNF or the TLR3 ligand poly I:C and abolish...

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“…Similarly, TNF-a, an agonist of the classical NF-kB pathway, has been shown to activate the alternative NF-kB pathway in murine embryonic fibroblasts (34,35). These findings demonstrate that multiple ligands previously considered as unique activators of either classical or alternative NF-kB can indeed activate both pathways.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

Tully

Nolin²,

Guala³

et al. 2012

Am J Respir Cell Mol Biol

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The transcription factor NF-kB has been causally linked to inflammatory lung diseases. Recent studies have unraveled the complexity of NF-kB activation by identifying two parallel activation pathways: the classical NF-kB pathway, which is controlled by IkB kinase complex-b (IKKb) and RelA/p50, and the alternative pathway, which is controlled by IKKa and RelB/p52. The alternative pathway regulates adaptive immune responses and lymphoid development, yet its role in the regulation of innate immune responses remains largely unknown. In this study, we determined the relevance of the alternative NF-kB pathway in proinflammatory responses in lung epithelial cells. The exposure of C10 murine alveolar lung epithelial cells to diverse stimuli, or primary murine tracheal epithelial cells to LPS, resulted in the activation of both NF-kB pathways, based on the nuclear translocation of RelA, p50, RelB, and p52. Increases in the nuclear content of RelA occurred rapidly, but transiently, whereas increases in nuclear RelB content were protracted. The small interfering (si) RNAmediated knockdown of IKKa, RelA, or RelB resulted in decreases of multiple LPS-induced proinflammatory cytokines. Surprisingly, the siRNA ablation of IKKa or RelB led to marked increases in the production of IL-6 in response to LPS. The simultaneous expression of constitutively active (CA)-IKKa and CA-IKKb caused synergistic increases in proinflammatory mediators. Lastly, the disruption of the IKK signalsome inhibited the activation of both NF-kB pathways. These results demonstrate that the coordinated activation of both NF-kB pathways regulates the magnitude and nature of proinflammatory responses in lung epithelial cells.Keywords: lung; IkB kinase-b; IkB kinase-a; RelA; RelB NF-kB is a transcription factor that plays a cardinal role in multiple cellular processes, including survival, proliferation, and inflammation. In unstimulated cells, NF-kB dimers RelA and p50 are sequestered in the cytosol by the inhibitor of kB (IkBa). The IkB kinase complex (IKK) consists of two catalytic subunits, IKKb and IKKa, and the regulatory protein, IKKg (also known as NF-kB essential modulator). Upon ligation by a variety of stimuli such as TNF-a or Toll-like receptor agonists, IKKb is phosphorylated and in turn phosphorylates IkBa, leading to its subsequent ubiquitination and degradation by the 26S proteasome (1, 2). The processing of IkBa promotes the nuclear translocation of RelA/p50, leading to the transcriptional activation of NF-kB-dependent genes. NF-kB activates the transcription of many proinflammatory cytokine and chemokine genes that initiate and propagate innate immune responses (1, 2).The airway epithelium, classically regarded as the first line of defense against inhaled agents, toxic factors, and physical trauma, is now recognized as a key component of the innate immune system, and plays an active role in the orchestration of acute inflammatory and adaptive immune responses (3, 4). Upon stimulation, epithelial cells secrete proinflammatory mediators such as...

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TNFα-induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2

Cited by 48 publications

References 57 publications

Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus

Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus

Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis

Cooperation between Classical and Alternative NF-κB Pathways Regulates Proinflammatory Responses in Epithelial Cells

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