TY - JOUR
T1 - Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria
AU - Singh, Sudha B.
AU - Ornatowski, Wojciech
AU - Vergne, Isabelle
AU - Naylor, John
AU - Delgado, Monica
AU - Roberts, Esteban
AU - Ponpuak, Marisa
AU - Master, Sharon
AU - Pilli, Manohar
AU - White, Eileen
AU - Komatsu, Masaaki
AU - Deretic, Vojo
N1 - Funding Information:
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.
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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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U2 - 10.1038/ncb2119
DO - 10.1038/ncb2119
M3 - Article
C2 - 21102437
AN - SCOPUS:78649833818
SN - 1465-7392
VL - 12
SP - 1154
EP - 1165
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 12
ER -