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First published online August 19, 2009
doi: 10.1242/10.1242/jcs.051193

Journal of Cell Science 122, 3161-3168 (2009)
Published by The Company of Biologists 2009
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Research Article

An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix

Damien Arnoult1,*,{ddagger}, Fraser Soares2,*, Ivan Tattoli2,3, Céline Castanier1, Dana J. Philpott3 and Stephen E. Girardin2,{ddagger}

1 INSERM U542, Hôpital Paul Brousse, Batiment Lavoisier, 14 avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France
2 Department of Laboratory Medicine and Pathobiology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
3 Department of Immunology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

{ddagger} Authors for correspondence (Damien.arnoult{at}inserm.fr; Stephen.girardin{at}utoronto.ca)

Accepted 20 June 2009

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 NF{kappa}B- 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, {Delta}{Psi}m. 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.

Key words: MAVS, Nod-like receptors, Antiviral signaling, Innate immunity, Mitochondria


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JCS 2009 122: 1704. [Full Text]  





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