Innate immunity relies on the detection of conserved microbial structures by pattern recognition molecules (PRMs). NLRX1 is a PRM that was initially shown to localise to the mitochondrial outer membrane (MOM) and to modulate the function of mitochondrial antiviral signalling protein (MAVS), which is anchored in the MOM through its transmembrane (TM) domain. However, Stephen Girardin and colleagues () now report new findings that refute these previous data. They use in silico analyses to show that NLRX1 contains an N-terminal mitochondrial targeting sequence but not a TM domain, which are characteristics typical of proteins that localise to the mitochondrial matrix but not to the MOM. Biochemical analyses support these predictions and show that NLRX1 strongly associates with the matrix side of the mitochondrial inner membrane (MIM). Similar to other MIM proteins, NLRX1 is targeted to the mitochondrial matrix only in the presence of an intact MIM potential (ΔΨm) and is proteolytically processed at this site by mitochondrial processing peptidases. But how does NLRX1 mediate innate immune function if it is located in the mitochondrial matrix? NLRX1 is also shown to associate with UQCRC2, a MIM component of the respiratory chain complex III required for the generation of reactive oxygen species; the authors propose that this association may underlie the innate immune activity of NLRX1.
