title: An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix.
abstract: NLRX1 is the only member of the Nod-like receptor (NLR) family that is targeted to the mitochondria, and its overexpression induces the generation of reactive oxygen species (ROS), thus impacting on NFkappaB- and JNK-dependent signaling cascades. In addition, NLRX1 has been shown to interact with MAVS (also known as IPS-1, VISA and Cardif) at the mitochondrial outer membrane and to modulate antiviral responses. Here we report that NLRX1 has a functional leader sequence and fully translocates to the mitochondrial matrix via a mechanism requiring the mitochondrial inner-membrane potential, DeltaPsim. Importantly, we failed to detect NLRX1 at the mitochondrial outer membrane. We also show that the leader sequence of NLRX1 is removed, which generates a mature protein lacking the first 39 amino acids through a maturation process that is common for mitochondrial-matrix proteins. Finally, we identified UQCRC2, a matrix-facing protein of the respiratory chain complex III, as an NLRX1-interacting molecule, thus providing a molecular basis for the role of NLRX1 in ROS generation. These results provide the first identification of a protein belonging to the NLR family that is targeted to the mitochondrial matrix.
authors.affiliation: INSERM U542, Hôpital Paul Brousse, Batiment Lavoisier, Villejuif Cedex, France. Damien.arnoult@inserm.fr
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Fraser
authors.initials: F
authors.lastname: Soares
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.forename: Céline
authors.initials: C
authors.lastname: Castanier
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
mesh_terms: D020816:Amino Acid Motifs; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D021381:Protein Transport
chemical_list: D024101:Mitochondrial Proteins; C527006:NLRX1 protein, human; D021382:Protein Sorting Signals
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