title: Cutting edge: NLRC5-dependent activation of the inflammasome.
abstract: The nucleotide-binding domain leucine-rich repeat-containing proteins, NLRs, are intracellular sensors of pathogen-associated molecular patterns and damage-associated molecular patterns. A subgroup of NLRs can form inflammasome complexes, which facilitate the maturation of procaspase 1 to caspase 1, leading to IL-1β and IL-18 cleavage and secretion. NLRC5 is predominantly expressed in hematopoietic cells and has not been studied for inflammasome function. RNA interference-mediated knockdown of NLRC5 nearly eliminated caspase 1, IL-1β, and IL-18 processing in response to bacterial infection, pathogen-associated molecular patterns, and damage-associated molecular patterns. This was confirmed in primary human monocytic cells. NLRC5, together with procaspase 1, pro-IL-1β, and the inflammasome adaptor ASC, reconstituted inflammasome activity that showed cooperativity with NLRP3. The range of pathogens that activate NLRC5 inflammasome overlaps with those that activate NLRP3. Furthermore, NLRC5 biochemically associates with NLRP3 in a nucleotide-binding domain-dependent but leucine-rich repeat-inhibitory fashion. These results invoke a model in which NLRC5 interacts with NLRP3 to cooperatively activate the inflammasome.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Reid A
authors.initials: RA
authors.lastname: Roberts
authors.forename: Max T
authors.initials: MT
authors.lastname: Huang
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Conti
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.forename: Brianne R
authors.initials: BR
authors.lastname: Barker
authors.forename: Mildred
authors.initials: M
authors.lastname: Kwan
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Accavitti-Loper
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007930:Leucine / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary / Q000235:genetics; D012763:Shigella flexneri / Q000276:immunology / Q000472:pathogenicity; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C548042:NLRC5 protein, human; C453881:NLRP3 protein, human; D007930:Leucine