A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion.

Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr 12, Kiel, Germany.
Journal of Cell Science (Impact Factor: 5.33). 03/2008; 121(Pt 4):487-95. DOI: 10.1242/jcs.016980
Source: PubMed

ABSTRACT NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide. Mutations in the leucine-rich repeat region of NOD2, which lead to an impaired recognition of muramyl dipeptide, have been associated with chronic inflammatory diseases of barrier organs such as Crohn disease, asthma and atopic eczema. In this study we identify CD147 (also known as BSG and EMMPRIN), a membrane-bound regulator of cellular migration, differentiation and inflammatory processes, as a protein interaction partner of NOD2. We demonstrate a complex influence of the CD147-NOD2 interaction on NOD2-dependent signaling responses. We show that CD147 itself acts as an enhancer of the invasion of Listeria monocytogenes, an intracellular bacterial pathogen. We propose that the CD147-NOD2 interaction serves as a molecular guide to regulate NOD2 function at sites of pathogen invasion.

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    • "NOD2 regulates the production of inflammatory mediators in response to muramyl dipeptide (MDP) which is found in Gram-negative and Gram-positive bacteria and mycobacteria (Girardin et al., 2003; Coulombe et al., 2009). Many studies have found that NOD2 is able to recognize and generate a response to a variety of microorganisms (Opitz et al., 2004; Ferwerda et al., 2005; Kobayashi et al., 2005; Herskovits et al., 2007; Kapetanovic et al., 2007; Hsu et al., 2008; Kim et al., 2008; Till et al., 2008; Deshmukh et al., 2009; Hruz et al., 2009; Loving et al., 2009). NOD2 senses bacteria through its leucinerich repeats (LRR), then oligomerizes through its NOD domain and is able to recruit receptor interacting protein 2 (RIP2) through an electrostatic interaction of the CARD domain in each protein. "
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    ABSTRACT: Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular pathogen of macrophages. Intracellular pattern recognition receptors in macrophages such as nucleotide-binding oligomerization domain (NOD) proteins regulate pro-inflammatory cytokine production. NOD2-mediated signalling pathways in response to M.tb have been studied primarily in mouse models and cell lines but not in primary human macrophages. Thus we sought to determine the role of NOD2 in regulating cytokine production and growth of virulent M.tb and attenuated Mycobacterium bovis BCG (BCG) in human macrophages. We examined NOD2 expression during monocyte differentiation and observed a marked increase in NOD2 transcript and protein following 2-3 days in culture. Pre-treatment of human monocyte-derived and alveolar macrophages with the NOD2 ligand muramyl dipeptide enhanced production of TNF-α and IL-1β in response to M.tb and BCG in a RIP2-dependent fashion. The NOD2-mediated cytokine response was significantly reduced following knock-down of NOD2 expression by using small interfering RNA (siRNA) in human macrophages. Finally, NOD2 controlled the growth of both M.tb and BCG in human macrophages, whereas controlling only BCG growth in murine macrophages. Together, our results provide evidence that NOD2 is an important intracellular receptor in regulating the host response to M.tb and BCG infection in human macrophages.
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    • "EGFP-NOD2 fusion protein was generated by inserting the NOD2 coding sequence into pEGFP-C3 vector using the HindIII and BamHI restriction sites. Overexpression constructs for individual NOD2 domains (CARDs, NBD, LRR) have been reported previously (Till et al., 2008). Overexpression constructs for DUOX2, DUOX2-HA and DUOXA2 have been described previously (Grasberger and Refetoff, 2006). "
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    ABSTRACT: Generation of microbicidal reactive oxygen species (ROS) is a pivotal protective component of the innate immune system in many eukaryotes. NOD (nucleotide oligomerisation domain containing protein)-like receptors (NLRs) have been implicated as phylogenetically ancient sensors of intracellular pathogens or endogenous danger signals. NOD2 recognizes the bacterial cell wall component muramyldipeptide leading to NFkappaB and MAPK activation via induced proximity signalling through the serine-threonine kinase RIP2. In addition to the subsequent induction of cytokines and antimicrobial peptides, NOD2 has been shown also to exert a direct antibacterial effect. Using a fluorescence-based ROS detection assay we demonstrate controlled ROS generation as an integral component of NOD2-induced signalling in epithelial cells. We demonstrate that the NAD(P)H oxidase family member DUOX2 is involved in NOD2-dependent ROS production. Coimmunoprecipitation and fluorescence microscopy were used to show that DUOX2 interacts and colocalizes with NOD2 at the plasma membrane. Moreover, simultaneous overexpression of NOD2 and DUOX2 was found to result in cooperative protection against bacterial cytoinvasion using the Listeria monocytogenes infection model. RNAi-based studies revealed that DUOX2 is required for the direct bactericidal properties of NOD2. Our results demonstrate a new role of ROS as effector molecules of protective cellular signalling in response to a defined danger signal carried out by a mammalian intracellular NLR system.
    Journal of Cell Science 10/2009; 122(Pt 19):3522-30. DOI:10.1242/jcs.050690 · 5.33 Impact Factor
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