NLRP1 activation by UVB: Shedding light on an enigmatic inflammasome

Abstract

In this issue of JEM, Jenster et al. (2022. J. Exp. Med. https://doi.org/10.1084/jem.20220837) investigate how UVB radiation promotes activation of the inflammatory immune sensor NLRP1, and in doing so uncover how NLRP1 recognizes a diverse range of ribotoxic stresses.

Insights from Andrew Sandstrom.

NLRP1 recognizes UVB radiation, ribotoxic stress, and viral infection via MAPK cascade. (A) Schematic of human NLRP1 domain architecture. (B) (1a) UVB radiation or certain antibiotics induce ribotoxic stress and activate ZAKα. (1b) Viral infection or CpG also induce activation of ZAKα. Phosphorylated ZAKα promotes phosphorylation of multiple p38 isoforms via MAPK signaling cascade. Active p38 phosphorylates the N-terminal linker between the PYD and NBD of NLRP1, promoting NLRP1 activation in a proteasome-dependent mechanism. Alternatively, neither activation of NLRP1 after cleavage and N-end rule mediated ubiquitination (Ub; 2) nor destabilization of the inhibitory DPP9 complex (3) require MAPK signaling to promote NLRP1 activation. SFV, Semliki Forst virus; SINV, Sinbdis virus.