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.

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    • "RIP2 which could have an additive effect on the activation of the MAPK pathway [39]. We also noted in vitro that PLA(NOD2)-p24 significantly increased the secretion of the proinflammatory cytokines IL-1b and TNFa, pro-T H 1 (IFNg, IL-12, GM-CSF) and pro-T H 2 (IL-6) cytokines as well as the chemokines CCL5 (RANTES), MIP-1a (CCL3), MIP-1b (CCL4) a chemoattractant for natural killer cells, monocytes and a variety of other immune cells [40]. "
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    ABSTRACT: Mucosal surfaces are a major portal of entry for many pathogens that are the cause of infectious diseases. Therefore, effective vaccines that induce a protective immune response at these sites are much needed. However, despite early success with the live attenuated oral polio vaccine over 50 years ago, only a few new mucosal vaccines have been subsequently licensed. Development of new adjuvants, comprising antigen delivery platforms and immunostimulatory molecules, are critical for the successful development of new mucosal vaccines. Among them, biodegradable nanoparticle delivery systems are promising and NOD-like receptors are considered as potential new targets for immunostimulatory molecules. In this work, different NOD1 and NOD2 ligands were encapsulated in polylactic acid (PLA) nanoparticles, coated with HIV-1 gag p24 antigen. We showed that these new formulations are able to induce proliferation of HIV-specific T cells from HIV+ individuals as well as autophagy. In vivo, these formulations highly enhanced p24-specific systemic and mucosal immune responses in mice not only after mucosal administration but also after immunization via the parenteral route. Our results provide a rational approach for combining nanosized particulate carriers and encapsulated NOD receptor ligands as potent synergistic tools for induction of specific mucosal immunity.
    Full-text · Article · Nov 2015 · Biomaterials
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    • "(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]. "
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    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.
    Full-text · Article · Jun 2014 · FEBS Letters
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    • "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]. "
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    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.
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