title: MDP-induced interleukin-1beta processing requires Nod2 and CIAS1/NALP3.
abstract: Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome 1 (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1beta, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP-induced IL-1beta release requires Nod2 and CIAS1/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, MDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-1beta production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Pan
authors.forename: John
authors.initials: J
authors.lastname: Mathison
authors.forename: Colleen
authors.initials: C
authors.lastname: Fearns
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kravchenko
authors.forename: Jean
authors.initials: J
authors.lastname: Da Silva Correia
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Grant
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ogura
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D007249:Inflammation; D053583:Interleukin-1beta / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse