ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome.
basic_science · Level V
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- Record sourced from PubMed, PMID 35857590.
- Also identified by DOI 10.1126/science.abl6324 and PMC identifier 7614315.
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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 (NLRP1<sup>DR</sup>) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1<sup>DR</sup> abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1<sup>DR</sup> 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.
Medical subject headings
- Inflammasomes
- MAP Kinase Kinase Kinases
- NLR Proteins
- Pyroptosis
- Ribosomes
- Stress, Physiological