The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathways

Zhao, Tiejun; Yang, Long; Sun, Qiang; Arguello, Meztli; Ballard, Dean W.; Hiscott, John; Lin, Rongtuan

doi:10.1038/ni1465

Cited by 290 publications

(280 citation statements)

References 49 publications

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“…To confirm that nuclear translocation of p65/RelA was dependent on an intact signaling pathway, we treated NEMO À/À MEFs with TNF, because NEMO, the regulatory subunit of the Ikk kinase complex, is required for activation of NF-kB. 22 Consistent with published results, 23 in NEMO À/À MEFs p65/RelA failed to translocate to the nucleus after treatment with TNF ( Figure 1a). By contrast, when treated with TNF, p65/RelA translocated to the nucleus normally in both caspase-8 À/À and FLIP À/À MEFs, suggesting neither cell line has a defect in p65/RelA activation in response to TNF (Figure 1a).…”

Section: Resultssupporting

confidence: 74%

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

et al. 2011

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Binding of TNF to TNF receptor-1 can give a pro-survival signal through activation of p65/RelA NF-jB, but also signals cell death. To determine the roles of FLICE-inhibitory protein (FLIP) and caspase-8 in TNF-induced activation of NF-jB and apoptosis, we used mouse embryonic fibroblasts derived from FLIP and caspase-8 gene-deleted mice, and treated them with TNF and a smac-mimetic compound that causes degradation of cellular inhibitor of apoptosis proteins (cIAPs). In cells treated with smac mimetic, TNF and Fas Ligand caused wild-type and FLIP À/À MEFs to die, whereas caspase-8 À/À MEFs survived, indicating that caspase-8 is necessary for death of MEFs triggered by these ligands when IAPs are degraded. By contrast, neither caspase-8 nor FLIP was required for TNF to activate p65/RelA NF-jB, because IjB was degraded, p65 translocated to the nucleus, and an NF-jB reporter gene activated normally in caspase-8 À/À or FLIP À/À MEFs. Reconstitution of FLIP À/À MEFs with the FLIP isoforms FLIP-L, FLIP-R, or FLIP-p43 protected these cells from dying when treated with TNF or FasL, whether or not cIAPs were depleted. These results show that in MEFs, caspase-8 is necessary for TNF-and FasL-induced death, and FLIP is needed to prevent it, but neither caspase-8 nor FLIP is required for TNF to activate NF-jB. Ligation of members of the TNF receptor superfamily typically triggers activation of transcription factors such as NF-kB, as well as proteins that can lead to cell death, such as RIPK1 and caspase-8. 1,2 The regulatory pathways that culminate in a pro-survival or apoptosis signal depend on the specific receptor that is ligated and the actions of proteins that transduce and modulate the signals flowing from it. For example, cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) and TNF receptor-associated factors (TRAF2 and TRAF3) are needed to prevent apoptosis of cells exposed to TNF, and favor activation of canonical (p65/RelA) NF-kB versus non-canonical (p100) NF-kB2. [3][4][5] Although TNF alone does not kill wild-type (WT) MEFs, it does cause apoptosis of MEFs in which genes for TRAF2 or p65/RelA NF-kB are deleted. 6 TNF can also kill MEFs that are mutant for cIAP1, and those in which cIAPs are depleted owing to treatment with a synthetic IAP antagonist 'smac-mimetic' compound. 7 These experiments indicate that pathways requiring cIAPs, TRAF2, and p65/RelA are normally able to block TNF-induced pro-apoptotic signals. Because treatment of cells with the translational inhibitor cycloheximide also sensitizes MEFs to killing by TNF, these experiments suggest that NF-kB drives the expression of cell death-inhibitory genes. 8 One of the NF-kB-regulated genes that is proposed to inhibit TNF-induced apoptosis is FLICE-inhibitory protein (FLIP). FLIP is structurally related to caspase-8. Like caspase-8, FLIP's N-terminus contains two death effector domains (DEDs), and its C-terminus has a caspase-like domain that is proteolytically inactive. 9 Transcripts from the murine FLIP gene can undergo alternative splicing to pro...

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Section: Resultssupporting

confidence: 74%

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

et al. 2011

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“…The absence of NEMO can therefore lead to uncontrolled virus replication. 12 The interaction of ubiquitin oligomers with NEMO activates IKKα and IKKβ by phosphorylation, leading to IκB-α phosphorylation and subsequent NF-κB activation. 50,51 NEMO can bind to TANK, TBK1 and IKKε by forming a complex to phosphorylate Ser172 of TBK1 and IRF3, which leads to IFN production.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 The absence of NEMO impedes the IRF3 phosphorylation and type-I IFN production induced by Sendai virus infection. 12 The RUN domain Beclin-1-interacting cysteine-rich-containing (Rubicon) protein was recently identified as a Beclin-1-binding partner that localizes to the late endosome/lysosome and negatively regulates the maturation step of autophagy and the endocytic pathway. 13,14 Under normal and stressful conditions, Rubicon primarily associates with the Beclin-1-containing autophagy complex.…”

Section: Introductionmentioning

confidence: 99%

Inducible Rubicon facilitates viral replication by antagonizing interferon production

et al. 2017

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The RUN domain Beclin-1-interacting cysteine-rich-containing (Rubicon) protein is involved in the maturation step of autophagy and the endocytic pathway as a Beclin-1-binding partner, but little is known regarding the role of Rubicon during viral infection. Here, we performed functional studies of the identified target in interferon (IFN) signaling pathways associated with Rubicon to elucidate the mechanisms of viral resistance to IFN. The Rubicon protein levels were elevated in peripheral blood mononuclear cells, sera and liver tissues from patients with hepatitis B virus (HBV) infection relative to those in healthy individuals. Assays of the overexpression and knockdown of Rubicon showed that Rubicon significantly promoted HBV replication. In addition, Rubicon knockdown resulted in the inhibition of enterovirus 71, influenza A virus and vesicular stomatitis virus. The expression o0f Rubicon led to the suppression of virus-induced type-I interferon (IFN-α and IFN-β) and type-III interferon (IFN-λ1). Translocation of activated IRF3 and IRF7 from the cytoplasm to the nucleus was involved in this process, and the NF-κB essential modulator (NEMO), a key factor in the IFN pathway, was the target with which Rubicon interacted. Our results reveal a previously unrecognized function of Rubicon as a virus-induced protein that binds to NEMO, leading to the inhibition of type-I interferon production. Rubicon thus functions as an important negative regulator of the innate immune response, enhances viral replication and may play a role in viral immune evasion.

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“…These results suggest that PI3K and NF-κB are involved in amylin upregulation by TNF-α. To further confirm that NF-κB activation is involved in the induction of amylin expression by TNF-α, we transfected MIN6 cells or mouse pancreatic islets with an Nfkbia dominant-negative construct (Nfkbia-DN) [32] or control vector flag-zeo. Overexpression of Nfkbia-DN in MIN6 cells (Fig.…”

Section: Tnf-α Induces Murine Amylin Expressionmentioning

confidence: 99%

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

Cai

Wang

et al. 2010

Diabetologia

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Aims/hypothesis Amylin, a secretory protein mainly produced by pancreatic beta cells, is elevated in the circulation of patients with diseases related to acute and chronic inflammation, including acute pancreatitis, pancreas graft rejection, obesity and insulin resistance. TNF-α is involved in these disorders. We investigated the effect of TNF-α on amylin levels and the underlying mechanisms, using murine pancreatic beta cell line MIN6 and pancreatic islets. Methods Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear factor κB (NF-κB) activation were examined by real-time PCR and luciferase reporter assay, respectively. Amylin protein level and mitogen-activated protein kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) activation was examined by electrophoretic mobility shift assay (EMSA).Results TNF-α acutely induced amylin expression at the transcriptional level and increased proamylin and the intermediate form of amylin in MIN6 cells and islets. However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) or protein kinase CK PKC ð z Þ, (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-α induced amylin expression through the PKC z Àextracellular signal-regulated kinase (ERK)/JNK pathways. EMSA showed that PKC z , JNK and ERK1/2 were involved in TNF-α-induced AP1 activation, suggesting that TNF-α induces murine amylin expression through the PKC z ÀERK1=2ÀAP1 and PKC z À JNKÀAP1 pathways. Further studies showed that TNF-α also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-κB signalling pathway and enhanced human amylin promoter activation through NF-κB and AP1. Conclusions/interpretation TNF-α acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders.

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The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathways

Cited by 290 publications

References 49 publications

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

Inducible Rubicon facilitates viral replication by antagonizing interferon production

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

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