The structure of NLRP9 reveals a unique C‐terminal region with putative regulatory function

• Published in: FEBS letters 2022-04, Vol.596 (7), p.876-885
• Main Authors: Kamitsukasa, Yukie, Nakano, Kenji, Murakami, Karin, Hirata, Kunio, Yamamoto, Masaki, Shimizu, Toshiyuki, Ohto, Umeharu
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins; Cattle; Cryoelectron Microscopy; cryo‐electron microscopy; Immunity, Innate; inflammasome; Inflammasomes - metabolism; Interleukin-1beta - metabolism; NLR; NLR Proteins - chemistry; X‐ray crystallography
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14302

Nucleotide‐binding and oligomerisation domain‐like receptors (NLRs) can form inflammasomes that activate caspase‐1 and pro‐interleukin‐1β and induce pyroptosis. NLR family pyrin domain‐containing 9 (NLRP9) forms an inflammasome and activates innate immune responses during virus infection, but little is known about this process. Here, we report the crystal and cryo‐electron microscopy structures of NLRP9 in an ADP‐bound state, revealing inactive and closed conformations of NLRP9 and its similarities to other structurally characterised NLRs. Moreover, we found a C‐terminal region interacting with the concave surface of the leucine‐rich repeat domain of NLRP9. This region is unique among NLRs and might be involved in the specific function of NLRP9. These data provide the structural basis for understanding the mechanism of NLRP9 regulation and activation. Nucleotide‐binding and oligomerisation domain‐like receptor family pyrin domain‐containing 9 (NLRP9) forms an inflammasome and activates innate immune responses during virus infection. The structure of NLRP9 in an ADP‐bound state reveals an inactive and closed conformation of NLRP9 and identifies a unique C‐terminal region that might be involved in the specific function of NLRP9.