ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome.
Science
; 377(6603): 328-335, 2022 07 15.
Article
em En
| MEDLINE
| ID: mdl-35857590
ABSTRACT
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ribossomos
/
Estresse Fisiológico
/
MAP Quinase Quinase Quinases
/
Inflamassomos
/
Piroptose
/
Proteínas NLR
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2022
Tipo de documento:
Article