Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 USA.
Nat Cell Biol. 2010 Dec;12(12):1154-65. doi: 10.1038/ncb2119. Epub 2010 Nov 21.
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.
IRGM，一种人类免疫相关 GTPase，通过未知机制赋予自噬防御以抵抗细胞内病原体。在这里，我们报告了 IRGM 作用的一种意外模式。IRGM 对线粒体脂质心磷脂表现出不同的亲和力，心磷脂易位到线粒体，影响线粒体裂变并诱导自噬。线粒体裂变对于 IRGM 控制细胞内分枝杆菌的自噬是必需的。IRGM 影响线粒体膜极化和细胞死亡。IRGMd 剪接异构体的过表达会导致线粒体去极化和 Bax/Bak 依赖性、自噬非依赖性的细胞死亡。通过作用于线粒体，IRGM 赋予自噬保护或细胞死亡，这解释了 IRGM 在防御结核病和克罗恩病引起的破坏性炎症中的作用。
