In this study, we analyzed the signaling cascades upstream of NLRP1 and revealed a unified signaling pathway that activates NLRP1 in response to diverse cell stress signals: Both activation of the ribotoxic stress response, as well as viral infections, trigger activation of p38 MAPKs, which then phosphorylate the linker region of NLRP1 and thus initiate the ubiquitination of the NLRP1PYD, followed by N-terminal degradation and nucleation of inflammasomes by the C-terminal NLRP1UPA-CARD. Here, NLRP1 is linked to viral infectious disease.