Browsing by Author "Sharon Master"

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    Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria
    (2010-12-01) Sudha B. Singh; Wojciech Ornatowski; Isabelle Vergne; John Naylor; Monica Delgado; Esteban Roberts; Marisa Ponpuak; Sharon Master; Manohar Pilli; Eileen White; Masaaki Komatsu; Vojo Deretic; University of New Mexico Health Sciences Center; Mahidol University; The Cancer Institute of New Jersey; Tokyo Metropolitan Institute of Medical Science; Juntendo University School of Medicine
    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. © 2010 Macmillan Publishers Limited. All rights reserved.
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    TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation
    (2012-08-24) Manohar Pilli; John Arko-Mensah; Marisa Ponpuak; Esteban Roberts; Sharon Master; Michael A. Mandell; Nicolas Dupont; Wojciech Ornatowski; Shanya Jiang; Steven B. Bradfute; Jack Ansgar Bruun; Tom Egil Hansen; Terje Johansen; Vojo Deretic; University of New Mexico Health Sciences Center; Mahidol University; Universitetet i Tromso
    Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles. © 2012 Elsevier Inc.