title: ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides.
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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences (DGP), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Radian
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Khare
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences (DGP), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Lan H
authors.initials: LH
authors.lastname: Chu
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: a-dorfleutner@northwestern.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dorfleutner
authors.affiliation: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: c-stehlik@northwestern.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Stehlik
mesh_terms: D000215:Acylation; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013203:Staphylococcal Infections / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058847:Inflammasomes; D053583:Interleukin-1beta; D055666:Lipopeptides; C502448:NLRP7 protein, human; D000255:Adenosine Triphosphate
keywords: ATPase; Caspase-1; IL-1β; Inflammation; Nod like receptor; Staphylococcus aureus