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  • Proceedings of the National Academy of Sciences  (47)
  • 1
    Online-Ressource
    Online-Ressource
    Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 30 ( 2013-07-23), p. 12379-12384
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 30 ( 2013-07-23), p. 12379-12384
    Kurzfassung: When host cells are infected by an RNA virus, pattern-recognition receptors (PRRs) recognize the viral RNA and induce the antiviral innate immunity. Toll-like receptor 7 (TLR7) detects the genomic RNA of incoming murine leukemia virus (MLV) in endosomes and mediates the antiviral response. However, the RNA-sensing PRR that recognizes the MLV in the cytosol is not fully understood. Here, we definitively demonstrate that zinc-finger antiviral protein (ZAP) acts as a cytosolic RNA sensor, inducing the degradation of the MLV transcripts by the exosome, an RNA degradation system, on RNA granules. Although the retinoic acid inducible gene I (RIG-I)–like receptors (RLRs) RIG-I and melanoma differentiation-associated protein 5 detect various RNA viruses in the cytosol and induce the type I IFN-dependent antiviral response, RLR loss does not alter the replication efficiency of MLV. In sharp contrast, the loss of ZAP greatly enhances the replication efficiency of MLV. ZAP localizes to RNA granules, where the processing-body and stress-granule proteins assemble. ZAP induces the recruitment of the MLV transcripts and exosome components to the RNA granules. The CCCH-type zinc-finger domains of ZAP, which are RNA-binding motifs, mediate its localization to RNA granules and MLV transcripts degradation by the exosome. Although ZAP was known as a regulator of RIG-I signaling in a human cell line, ZAP deficiency does not affect the RIG-I–dependent production of type I IFN in mouse cells. Thus, ZAP is a unique member of the cytosolic RNA-sensing PRR family that targets and eliminates intracellular RNA viruses independently of TLR and RLR family members.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1310604110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2013
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Nitric oxide-induced apoptosis in pancreatic β cells is mediated by the endoplasmic reticulum stress pathway
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 19 ( 2001-09-11), p. 10845-10850
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 19 ( 2001-09-11), p. 10845-10850
    Kurzfassung: Excessive nitric oxide (NO) production in cytokine-activated β cells has been implicated in β cell disruption in type 1 diabetes. β cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 β cells. CHOP, a C/EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor, S -nitroso- N -acetyl- d,l -penicillamine (SNAP). SNAP increased cytosolic Ca 2+ , and only agents depleting ER Ca 2+ induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca 2+ . Overexpression of calreticulin increased the Ca 2+ content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca 2+ , causes ER stress, and leads to apoptosis. Thus, ER Ca 2+ stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated β cell apoptosis.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.191207498
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2001
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK–STAT
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 47 ( 2005-11-22), p. 17089-17094
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 47 ( 2005-11-22), p. 17089-17094
    Kurzfassung: Suppressor of cytokine signaling-1 (SOCS-1) is one of the negative-feedback regulators of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We previously showed that SOCS-1 participates in LPS signaling, but it is not entirely clear yet how SOCS-1 suppresses LPS signaling. In this study, we demonstrate that SOCS-1 selectively inhibits LPS-induced IL-6 production through regulation of JAK–STAT but not production of TNF-α, granulocyte colony-stimulating factor, IFN-β, and other cytokines. We found that LPS directly activated Jak2 and Stat5, whereas SOCS-1 inhibited LPS-induced Jak2 and Stat5 activation. Furthermore, AG490, a Jak-specific inhibitor, and dominant negative Stat5 only reduced LPS-induced IL-6 production. Additionally, Stat5 interacted with p50, resulting in recruitment of Stat5 to the IL-6 promoter together with p50 in response to LPS stimulation. These findings suggest that the JAK–STAT pathway participates in LPS-induced IL-6 production and that SOCS-1 suppresses LPS signaling by regulating JAK–STAT.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0508517102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2005
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    LGP2 is a positive regulator of RIG-I– and MDA5-mediated antiviral responses
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 4 ( 2010-01-26), p. 1512-1517
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 4 ( 2010-01-26), p. 1512-1517
    Kurzfassung: RNA virus infection is recognized by retinoic acid-inducible gene (RIG)-I–like receptors (RLRs), RIG-I, and melanoma differentiation–associated gene 5 (MDA5) in the cytoplasm. RLRs are comprised of N-terminal caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain. The third member of the RLR family, LGP2, lacks any CARDs and was originally identified as a negative regulator of RLR signaling. In the present study, we generated mice lacking LGP2 and found that LGP2 was required for RIG-I– and MDA5-mediated antiviral responses. In particular, LGP2 was essential for type I IFN production in response to picornaviridae infection. Overexpression of the CARDs from RIG-I and MDA5 in Lgp2 −/− fibroblasts activated the IFN-β promoter, suggesting that LGP2 acts upstream of RIG-I and MDA5. We further examined the role of the LGP2 helicase domain by generating mice harboring a point mutation of Lys-30 to Ala ( Lgp2 K30A/K30A ) that abrogated the LGP2 ATPase activity. Lgp2 K30A/K30A dendritic cells showed impaired IFN-β productions in response to various RNA viruses to extents similar to those of Lgp2 −/− cells. Lgp2 −/− and Lgp2 K30A/K30A mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands for MDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0912986107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2010
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 5
    Online-Ressource
    Online-Ressource
    Contribution of IL-33–activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 9 ( 2012-02-28), p. 3451-3456
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 9 ( 2012-02-28), p. 3451-3456
    Kurzfassung: When animals are infected with helminthic parasites, resistant hosts show type II helper T immune responses to expel worms. Recently, natural helper (NH) cells or nuocytes, newly identified type II innate lymphoid cells, are shown to express ST2 (IL-33 receptor) and produce IL-5 and IL-13 when stimulated with IL-33. Here we show the relevant roles of endogenous IL-33 for Strongyloides venezuelensis infection-induced lung eosinophilic inflammation by using Il33 −/− mice. Alveolar epithelial type II cells (ATII) express IL-33 in their nucleus. Infection with S. venezuelensis or intranasal administration of chitin increases in the number of ATII cells and the level of IL-33. S. venezuelensis infection induces pulmonary accumulation of NH cells, which, after being stimulated with IL-33, proliferate and produce IL-5 and IL-13. Furthermore, S. venezuelensis infected Rag2 −/− mice increase the number of ATII cells, NH cells, and eosinophils and the expression of IL-33 in their lungs. Finally, IL-33–stimulated NH cells induce lung eosinophilic inflammation and might aid to expel infected worms in the lungs.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1201042109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2012
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 15 ( 2012-04-10), p. 5791-5796
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 15 ( 2012-04-10), p. 5791-5796
    Kurzfassung: Toll-like receptor 3 (TLR3) mediates antiviral response by recognizing double-stranded RNA. Its cytoplasmic domain is tyrosine phosphorylated upon ligand binding and initiates downstream signaling via the adapter TIR-containing adaptor inducing interferon–β (TRIF). However, the kinase responsible for TLR3 phosphorylation remains unknown. We show here that Bruton's tyrosine kinase (BTK)-deficient macrophages failed to secrete inflammatory cytokines and IFN-β upon TLR3 stimulation and were impaired in clearing intracellular dengue virus infection. Mutant mice were also less susceptible to d -galactosamine/p(I:C)-induced sepsis. In the absence of BTK, TLR3-induced phosphoinositide 3-kinase (PI3K), AKT and MAPK signaling and activation of NFκB, IRF3, and AP-1 transcription factors were all defective. We demonstrate that BTK directly phosphorylates TLR3 and in particular the critical Tyr759 residue. BTK point mutations that abrogate or led to constitutive kinase activity have opposite effects on TLR3 phosphorylation. Loss of BTK also compromises the formation of the downstream TRIF/receptor-interacting protein 1 (RIP1)/TBK1 complex. Thus, BTK plays a critical role in initiating TLR3 signaling.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1119238109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2012
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 7
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    Online-Ressource
    Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 ( Irf2 ) in trypsinogen5 gene transcription
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 46 ( 2011-11-15), p. 18766-18771
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 46 ( 2011-11-15), p. 18766-18771
    Kurzfassung: Mice deficient for interferon regulatory factor ( Irf ) 2 ( Irf2 −/− mice) exhibit immunological abnormalities and cannot survive lymphocytic choriomeningitis virus infection. The pancreas of these animals is highly inflamed, a phenotype replicated by treatment with poly(I:C), a synthetic double-stranded RNA. Trypsinogen5 mRNA was constitutively up-regulated about 1,000-fold in Irf2 −/− mice compared with controls as assessed by quantitative RT-PCR. Further knockout of IFNα/β receptor 1 ( Ifnar1 ) abolished poly(I:C)-induced pancreatitis but had no effect on the constitutive up-regulation of trypsinogen5 gene, indicating crucial type I IFN signaling to elicit the inflammation. Analysis of Ifnar1 −/− mice confirmed type I IFN-dependent transcriptional activation of dsRNA-sensing pattern recognition receptor genes MDA5 , RIG-I , and TLR3 , which induced poly(I:C)-dependent cell death in acinar cells in the absence of IRF2. We speculate that Trypsin5, the trypsinogen5 gene product, leaking from dead acinar cells triggers a chain reaction leading to lethal pancreatitis in Irf2 −/− mice because it is resistant to a major endogenous trypsin inhibitor, Spink3.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1116273108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2011
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 49 ( 2009-12-08), p. 20842-20846
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 49 ( 2009-12-08), p. 20842-20846
    Kurzfassung: Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0911267106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2009
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 26 ( 2021-06-29)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 26 ( 2021-06-29)
    Kurzfassung: Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout ( Fchsd1 −/− ) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1 −/− mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1 −/− mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H 2 O 2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2019167118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2021
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 10
    Online-Ressource
    Online-Ressource
    Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 42 ( 2008-10-21), p. 16260-16265
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 42 ( 2008-10-21), p. 16260-16265
    Kurzfassung: Toll-like receptors (TLRs) may need to cooperate with each other to be effective in detecting imminent infection and trigger immune responses. Understanding is still limited about the intracellular mechanism of this cooperation. We found that when certain TLRs are involved, dendritic cells (DCs) establish unidirectional intracellular cross-talk, in which the MyD88-independent TRIF-dependent pathway amplifies the MyD88-dependent DC function through a JNK-dependent mechanism. The amplified MyD88-dependent DC function determines the induction of the T cell response to a given vaccine in vivo . Therefore, our study revealed an underlying TLR mechanism governing the functional, nonrandom interplay among TLRs for recognition of combinatorial ligands that may be dangerous to the host, providing important guidance for design of novel synergistic molecular vaccine adjuvants.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0805325105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2008
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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