Human NLRP1 is activated by ZAKɑ-driven ribotoxic stress response

ABSTRACT

Human NLRP1 is a multifunctional inflammasome sensor predominantly expressed in skin and airway epithelium; however its function in skin-specific immunity and its mechanisms of activation are not fully understood. Here we report that human NLRP1 is specifically activated by the ZAKɑ- driven ribotoxic stress response pathway (RSR) induced by ultraviolet B (UVB) irradiation or select microbial ribotoxins. Biochemically, RSR-triggered NLRP1 activation requires ZAKɑ- dependent hyperphosphorylation of a human-specific linker region of NLRP1 (NLRP1^DR), leading to the ‘functional degradation’ of the auto-inhibitory NLRP1 N-terminal fragment. Additionally, we show that fusing NLRP1^DR to the signaling domains of CARD8, which in itself is insensitive to RSR, creates a minimal inflammasome sensor for UVB and ribotoxins. In summary, these discoveries resolve the mechanisms of UVB sensing by human NLRP1, identify ZAKɑ-activating toxins as novel human NLRP1 activators, and establish NLRP1 inflammasome-dependent pyroptosis as an integral component of the ribotoxic stress response in primary human cells.

1. UVB-induced NLRP1 activation in human keratinocytes involves a nuclear DNA-independent stress response involving photodamaged RNA

2. ZAKɑ kinase is required for UVB-triggered, but not VbP- or dsRNA-induced human NLRP1 activation

3. ZAKɑ-activating microbial ribotoxins specifically activate the NLRP1 inflammasome in multiple primary human cell types

4. Hyperphosphorylation of a linker region (NLRP1^DR) is required for RSR-dependent human NLRP1 activation

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