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Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria

Nature Cell Biology volume 12, pages 1154–1165 (2010)Cite this article

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Abstract

IRGM, a human immunity-related GTPase, confers autophagic defence against intracellular pathogens by an unknown mechanism. Here, we report an unexpected mode of IRGM action. IRGM demonstrated differential affinity for the mitochondrial lipid cardiolipin, translocated to mitochondria, affected mitochondrial fission and induced autophagy. Mitochondrial fission was necessary for autophagic control of intracellular mycobacteria by IRGM. IRGM influenced mitochondrial membrane polarization and cell death. Overexpression of IRGMd, but not IRGMb splice isoforms, caused mitochondrial depolarization and autophagy-independent, but Bax/Bak-dependent, cell death. By acting on mitochondria, IRGM confers autophagic protection or cell death, explaining IRGM action both in defence against tuberculosis and in the damaging inflammation caused by Crohn's disease.

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Figure 1: IRGM localizes to mitochondria.
Figure 2: IRGM co-fractionates with mitochondria and localizes to their inner membrane or matrix.
Figure 3: IRGM affects mitochondrial fission.
Figure 4: Relationship between mitochondrial fission and autophagy and roles of IRGM, DRP1 and FIS1 in autophagic control of mycobacteria.
Figure 5: IRGMd binds to cardiolipin and causes loss of mitochondrial membrane potential.
Figure 6: IRGMd translocates to mitochondria, induces mitochondrial fragmentation and causes loss of mitochondrial ΔΨm independent of autophagic, but dependent on apoptotic, machinery.
Figure 7: IRGMd induces cell death.
Figure 8: Comparison of IRGMa, IRGMb and IRGMc effects.

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Acknowledgements

This work was supported by NIH grants AI069345, RC1AI086845 and AI42999, a grant from Crohn's & Colitis Foundation of America and a grant from the Bill and Melinda Gates Foundation.

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Author notes

  1. Sudha B. Singh and Wojciech Ornatowski: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, Albuquerque, NM 87131, NE, USA

    Sudha B. Singh, Wojciech Ornatowski, Isabelle Vergne, John Naylor, Monica Delgado, Esteban Roberts, Marisa Ponpuak, Sharon Master, Manohar Pilli & Vojo Deretic

  2. Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Marisa Ponpuak

  3. Department of Molecular Biology and Biochemistry, Cancer Institute of New Jersey, Rutgers University, CABM, 679 Hoes Lane, Piscataway, 08854, NJ, USA

    Eileen White

  4. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo, 113-8421, Japan

    Masaaki Komatsu

  5. Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Masaaki Komatsu

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Contributions

S.B.S., W.O., I.V., J.N., M.D., E.R., M.P. and S.M. carried out planning, experimental work and data analysis. E.W. and M.K. contributed MEFs and protocols for their use. V.D. carried out project planning, experimental work and wrote the manuscript.

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Correspondence to Vojo Deretic.

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Singh, S., Ornatowski, W., Vergne, I. et al. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol 12, 1154–1165 (2010). https://doi.org/10.1038/ncb2119

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