Human NLRP1 is activated by ZAKa-driven ribotoxic stress response

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 ZAK[a]- driven ribotoxic stress response pathway (RSR) induced by ultraviolet B (UVB) irradiation or select microbial ribotoxins. Biochemically, RSR-triggered NLRP1 activation requires ZAK[a]- dependent hyperphosphorylation of a human-specific linker region of NLRP1 (NLRP1DR), leading to the functional degradation of the auto-inhibitory NLRP1 N-terminal fragment. Additionally, we show that fusing NLRP1DR 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 ZAK[a]-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. O_LIUVB-induced NLRP1 activation in human keratinocytes involves a nuclear DNA-independent stress response involving photodamaged RNA C_LIO_LIZAK[a] kinase is required for UVB-triggered, but not VbP- or dsRNA-induced human NLRP1 activation C_LIO_LIZAK[a]-activating microbial ribotoxins specifically activate the NLRP1 inflammasome in multiple primary human cell types C_LIO_LIHyperphosphorylation of a linker region (NLRP1DR) is required for RSR-dependent human NLRP1 activation C_LI O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/477516v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@dea86aorg.highwire.dtl.DTLVardef@2eb7forg.highwire.dtl.DTLVardef@1b301bborg.highwire.dtl.DTLVardef@136aa32_HPS_FORMAT_FIGEXP M_FIG C_FIG