ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides |
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| Affiliation: | 1. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;2. Driskill Graduate Program in Life Sciences (DGP), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;3. Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;1. Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;2. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;3. Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;4. Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA;5. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA;6. UCLA AIDS Institute, Los Angeles, CA, USA;7. The Molecular Biology Institute, University of California, Los Angeles, CA, USA;1. Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India;2. Department of Human Physiology, University of Calcutta, 92, APC Road, Kolkata 700009, India;3. Laboratory of Virology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India;1. Institute of Biological and Environmental Sciences, University of Aberdeen, Tillydrone Avenue, Aberdeen, AB24 2TZ, UK;2. BioMar Ltd., Grangemouth Docks, Grangemouth FK3 8UL, UK;3. Institute of Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan, ROC;1. Institute of Medical Microbiology, University of Duisburg-Essen, 45147 Essen, Germany;2. Department of Chemistry, University of Natural Resources and Life Sciences, 1190 Vienna, Austria |
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| Abstract: | Nucleotide-binding oligimerization domain (NOD)-like receptors (NLRs) are pattern recognition receptors (PRRs) involved in innate immune responses. NLRs encode a central nucleotide-binding domain (NBD) consisting of the NAIP, CIITA, HET-E and TP1 (NACHT) domain and the NACHT associated domain (NAD), which facilitates receptor oligomerization and downstream inflammasome signaling. The NBD contains highly conserved regions, known as Walker motifs, that are required for nucleotide binding and hydrolysis. The NLR containing a PYRIN domain (PYD) 7 (NLRP7) has been recently shown to assemble an ASC and caspase-1-containing high molecular weight inflammasome complex in response to microbial acylated lipopeptides and Staphylococcus aureus infection. However, the molecular mechanism responsible for NLRP7 inflammasome activation is still elusive. Here we demonstrate that the NBD of NLRP7 is an ATP binding domain and has ATPase activity. We further show that an intact nucleotide-binding Walker A motif is required for NBD-mediated nucleotide binding and hydrolysis, oligomerization, and NLRP7 inflammasome formation and activity. Accordingly, THP-1 cells expressing a mutated Walker A motif display defective NLRP7 inflammasome activation, interleukin (IL)-1β release and pyroptosis in response to acylated lipopeptides and S. aureus infection. Taken together, our results provide novel insights into the mechanism of NLRP7 inflammasome assembly. |
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| Keywords: | Inflammation IL-1β Caspase-1 Nod like receptor ATPase |
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