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A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses.

ABSTRACT: Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Although over 20 of these proteins are present in humans, only a few members including the cytosolic pattern recognition receptors NOD1, NOD2, and NLRP3 have been analyzed extensively. These NLRs were shown to be pivotal for mounting innate immune response toward microbial invasion. Here we report on the characterization of human NLRC5 and provide evidence that this NLR has a function in innate immune responses. We found that NLRC5 is a cytosolic protein expressed predominantly in hematopoetic cells. NLRC5 mRNA and protein expression was inducible by the double-stranded RNA analog poly(I.C) and Sendai virus. Overexpression of NLRC5 failed to trigger inflammatory responses such as the NF-kappaB or interferon pathways in HEK293T cells. However, knockdown of endogenous NLRC5 reduced Sendai virus- and poly(I.C)-mediated type I interferon pathway-dependent responses in THP-1 cells and human primary dermal fibroblasts. Taken together, this defines a function for NLRC5 in anti-viral innate immune responses.

SUBMITTER: Neerincx A

PROVIDER: S-EPMC2924034 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses.

Neerincx Andreas A Lautz Katja K Menning Maureen M Kremmer Elisabeth E Zigrino Paola P Hösel Marianna M Büning Hildegard H Schwarzenbacher Robert R Kufer Thomas A TA

The Journal of biological chemistry 20100610 34

Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Although over 20 of these proteins are present in humans, only a few members including the cytosolic pattern recognition receptors NOD1, NOD2, and NLRP3 have been analyzed extensively. These NLRs were shown to be pivotal for mounting innate immune response toward microbial invasion. Here we report on the characterization of human NL ...[more]

PMID: 20538593

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Project description:UnlabelledBacterially induced osteoblast apoptosis may be a major contributor to bone loss during osteomyelitis. We provide evidence for the functional expression in osteoblasts of NLRP3, a member of the NLR family of cytosolic receptors that has been implicated in the initiation of programmed cell death.IntroductionOsteoblasts undergo apoptosis after exposure to intracellular bacterial pathogens commonly associated with osteomyelitis. Death of this bone-forming cell type, in conjunction with increased numbers and activity of osteoclasts, may underlie the destruction of bone tissue at sites of bacterial infection. To date, the mechanisms responsible for bacterially induced apoptotic osteoblast cell death have not been resolved.Materials and methodsWe used flow cytometric techniques to determine whether intracellular invasion is needed for maximal apoptotic cell death in primary osteoblasts after challenge with Salmonella enterica. In addition, we used real-time PCR and immunoblot analyses to assess osteoblast expression of members of the nucleotide-binding domain leucine-rich repeat region-containing family of intracellular receptors (NLRs) that have been predicted to be involved in the induction of programmed cell death. Furthermore, we have used co-immunoprecipitation and siRNA techniques to confirm the functionality of such sensors in this cell type.ResultsIn this study, we showed that invasion of osteoblasts by Salmonella is necessary for maximal induction of apoptosis. We showed that murine and human osteoblasts express NLRP3 (previously known as CIAS1, cryopyrin, PYPAF1, or NALP3) but not NLRC4 (IPAF) and showed that the level of expression of this cytosolic receptor is modulated after bacterial challenge. We showed that osteoblasts express ASC, an adaptor molecule for NLRP3, and that these molecules associate after Salmonella infection. In addition, we showed that a reduction in the expression of NLRP3 attenuates Salmonella-induced reductions in the activity of an anti-apoptotic transcription factor in osteoblasts. Furthermore, we showed that NLRP3 expression is needed for caspase-1 activation and maximal induction of apoptosis in osteoblasts after infection with Salmonella.ConclusionsThe functional expression of NLRP3 in osteoblasts provides a potential mechanism underlying apoptotic cell death of this cell type after challenge with intracellular bacterial pathogens and may be a significant contributory factor to bone loss at sites of infection.

Dataset Information

A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses.

Publications

A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses.

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