An orphan no more: Nur77 senses cytosolic LPS.

Cytosolic LPS activates the NLRP3 inflammasome via a gasdermin D (GSDMD)-dependent mechanism. In this issue of Immunity, Zhu et al.1 provide insight into the events linking these two steps, identifying the orphan nuclear receptor Nur77 as a mediator of NLRP3 activation that senses LPS and GSDMD-dependent accumulation of cytosolic mtDNA.