Hsu, Y.-M. S. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature Immunol. 8, 198-205

Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Nature Immunology (Impact Factor: 20). 03/2007; 8(2):198-205. DOI: 10.1038/ni1426
Source: PubMed


The caspase-recruitment domain-containing adaptor protein CARD9 regulates the innate signaling responses to fungal infection. Here we show that CARD9 is required for innate immune responses against intracellular pathogens. We generated Card9(-/-) mice and found that CARD9-deficient macrophages had defects in activation of the kinases p38 and Jnk but not of transcription factor NF-kappaB after bacterial and viral infection. CARD9-deficient mice failed to clear infection and showed altered cytokine production after challenge with Listeria monocytogenes. In wild-type cells, we found CARD9 inducibly associated with both the intracellular 'biosensor' Nod2 and the serine-threonine kinase RICK. Our data demonstrate that CARD9 has a critical function in Nod2-mediated activation of p38 and Jnk in innate immune responses to intracellular pathogens.

Download full-text


Available from: Donghai Wang, Oct 04, 2015
28 Reads
  • Source
    • "(2014), dipeptide or Listeria monocytogenes [17]. The association between NOD2 and CARD9 was enhanced by the presence of RIP2 in both over-expression and endogenous systems [17]. The relationship between CARD9 and NOD2 is particularly intriguing as the genes for both these proteins contain polymorphisms influencing susceptibility to Crohn's Disease in humans [18] [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself. Structured summary of protein interactions: NOD2 physically interacts with CARD9 by anti tag coimmunoprecipitation (View interaction) (C) 2014 The Authors. Published by Elsevier B.V.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.06.035 · 3.17 Impact Factor
  • Source
    • "RIPK2 is critical for NOD1- and NOD2-mediated NF-KB activation because NOD1 and NOD2 signaling is abolished in RIPK2-deficient cells [41]. In addition to the activation of the NF-KB pathway, NOD2 stimulation results in activation of the MAPKs p38, ERK and JNK [42]. 2) Alternative pathways which may or may not require RIPK2 include the induction of type I IFN and autophagy [24], [43]–[45]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nucleotide-binding oligomerization domain 2 (NOD2) is an important innate immune sensor of bacterial pathogens. Its induction results in activation of the classic NF-κB pathway and alternative pathways including type I IFN and autophagy. Although the importance of NOD2 in recognizing RNA viruses has recently been identified, its role in sensing DNA viruses has not been studied. We report that infection with human cytomegalovirus (HCMV) results in significant induction of NOD2 expression, beginning as early as 2 hours post infection and increasing steadily 24 hours post infection and afterwards. Infection with human herpesvirus 1 and 2 does not induce NOD2 expression. While the HCMV-encoded glycoprotein B is not required for NOD2 induction, a replication competent virion is necessary. Lentivirus-based NOD2 knockdown in human foreskin fibroblasts (HFFs) and U373 glioma cells leads to enhanced HCMV replication along with decreased levels of interferon beta (IFN-β) and the pro-inflammatory cytokine, IL8. NOD2 induction in HCMV-infected cells activates downstream NF-κB and interferon pathways supported by reduced nuclear localization of NF-κB and pIRF3 in NOD2 knockdown HFFs. Stable overexpression of NOD2 in HFFs restricts HCMV replication in association with increased levels of IFN-β and IL8. Similarly, transient overexpression of NOD2 in U373 cells or its downstream kinase, RIPK2, results in decreased HCMV replication and enhanced cytokine responses. However, overexpression of a mutant NOD2, 3020insC, associated with severe Crohn's disease, results in enhanced HCMV replication and decreased levels of IFN-β in U373 cells. These results show for the first time that NOD2 plays a significant role in HCMV replication and may provide a model for studies of HCMV recognition by the host cell and HCMV colitis in Crohn's disease.
    PLoS ONE 03/2014; 9(3):e92704. DOI:10.1371/journal.pone.0092704 · 3.23 Impact Factor
  • Source
    • "NOD-like receptor pathway adaptor protein, CARD9 was up regulated in all three groups (Figure 7 and 8). CARD9 plays a critical role in NOD2-mediated regulation of NF-κB and MAP kinase signaling leading to pro-inflammatory responses (Table S5) [23], [24]. Alteration of certain genes resulting in inhibition or regulation of NF-κB was observed as in case of CHUK (conserved helix-loop-helix ubiquitous kinase)/IKK1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenesis of hepatitis B virus (HBV) and hepatitis E virus (HEV) infection is as varied as they appear similar; while HBV causes an acute and/or chronic liver disease and hepatocellular carcinoma, HEV mostly causes an acute self-limiting disease. In both infections, host responses are crucial in disease establishment and/or virus clearance. In the wake of worsening prognosis described during HEV super-infection over chronic HBV hepatitis, we investigated the host responses by studying alterations in gene expression in liver cells (Huh-7 cell line) by transfection with HEV replicon only (HEV-only), HBV replicon only (HBV-only) and both HBV and HEV replicons (HBV+HEV). Virus replication was validated by strand-specific real-time RT-PCR for HEV and HBsAg ELISA of the culture supernatants for HBV. Indirect immunofluorescence for the respective viral proteins confirmed infection. Transcription profiling was carried out by RNA Sequencing (RNA-Seq) analysis of the poly-A enriched RNA from the transfected cells. Averages of 600 million bases within 5.6 million reads were sequenced in each sample and ∼15,800 genes were mapped with at least one or more reads. A total of 461 genes in HBV+HEV, 408 in HBV-only and 306 in HEV-only groups were differentially expressed as compared to mock transfection control by two folds (p<0.05) or more. Majority of the significant genes with altered expression clustered into immune-associated, signal transduction, and metabolic process categories. Differential gene expression of functionally important genes in these categories was also validated by real-time RT-PCR based relative gene-expression analysis. To our knowledge, this is the first report of in vitro replicon transfected RNA-Seq based transcriptome analysis to understand the host responses against HEV and HBV.
    PLoS ONE 02/2014; 9(2):e87835. DOI:10.1371/journal.pone.0087835 · 3.23 Impact Factor
Show more