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

• Published in: Nature cell biology Vol. 12; no. 12; pp. 1154 - 1165
• Main Authors: Singh, Sudha B., Ornatowski, Wojciech, Vergne, Isabelle, Naylor, John, Delgado, Monica, Roberts, Esteban, Ponpuak, Marisa, Master, Sharon, Pilli, Manohar, White, Eileen, Komatsu, Masaaki, Deretic, Vojo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2010; Nature Publishing Group
• Subjects: 631/250/262; 631/80/642/333; 631/80/82/39; Animals; Autophagy; Biochemistry; Biomedical and Life Sciences; Cancer Research; Cardiolipins - metabolism; Cell Biology; Cell death; Cell Line; Crohn's disease; Cytochrome; Developmental Biology; Dynamins; GTP Phosphohydrolases - metabolism; GTP-Binding Proteins - analysis; GTP-Binding Proteins - metabolism; Humans; Interferon; Life Sciences; Mice; Microscopy; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - chemistry; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Mortality; Pathogens; Protein Isoforms - metabolism; Sedimentation & deposition; Stem Cells; Tuberculosis; United States > US; Japan
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/ncb2119

IRGM is a human GTPase that triggers autophagy in response to pathogen infection. On Mycobacteria infection, IRGM binds the mitochondrial cardiolipin to induce mitochondrial fission and a general autophagy response. It can also trigger autophagy-independent mitochondria-mediated cell death. 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.