Abstract
In the present study, we investigated the role of nucleotide oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6) in rheumatoid arthritis (RA) and explored the underlying mechanism. We found that both mRNA and protein levels of NLRP6 are attenuated in synovial tissues and fibroblast-like synoviocytes (FLS) of RA patients compared to patients with osteoarthritis. We also observed that pro-inflammatory cytokine production is decreased and nuclear factor-kappa B activation is inhibited in NLRP6-overexpressing RA-FLS. Furthermore, we found that NLRP6 overexpression promotes transforming growth factor-b-activated kinase 1-binding protein 2/3 lysosome-dependent degradation, and we provide evidence showing that NLRP6 plays the role of providing the docking site to facilitate the interaction between transforming growth factor-b-activated kinase 1-binding protein 2/3 and tripartite motif 38 in RA-FLS.
Keywords:
NF-κB; NLRP6; TAB2/3; fibroblast-like synoviocytes; rheumatoid arthritis.
© 2017 Federation of European Biochemical Societies.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism*
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Arthritis, Rheumatoid / pathology
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism*
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Cells, Cultured
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Down-Regulation
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Genes, Reporter
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Humans
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Immunoprecipitation
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Interleukin-1beta / metabolism
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Osteoarthritis / immunology
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Osteoarthritis / metabolism
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Osteoarthritis / pathology
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Protein Interaction Domains and Motifs
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RNA Interference
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RNA, Messenger / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Synovial Membrane / immunology
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Synovial Membrane / metabolism
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Synovial Membrane / pathology
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Synoviocytes / immunology
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Synoviocytes / metabolism*
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Synoviocytes / pathology
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Tripartite Motif Proteins
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitin-Protein Ligases
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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IL1B protein, human
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IL6 protein, human
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Interleukin-1beta
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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NLRP6 protein, human
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RNA, Messenger
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Recombinant Proteins
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TAB2 protein, human
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TAB3 protein, human
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TNF protein, human
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Tripartite Motif Proteins
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Tumor Necrosis Factor-alpha
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TRIM38 protein, human
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Ubiquitin-Protein Ligases