The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy

Jayoung Choi; Sunmin Park; Scott B Biering; Elizabeth Selleck; Catherine Y Liu; Xin Zhang; Naonobu Fujita; Tatsuya Saitoh; Shizuo Akira; Tamotsu Yoshimori; L David Sibley; Seungmin Hwang; Herbert W Virgin

doi:10.1016/j.immuni.2014.05.006

The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy

Immunity. 2014 Jun 19;40(6):924-35. doi: 10.1016/j.immuni.2014.05.006. Epub 2014 Jun 12.

Authors

Affiliations

¹ Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
³ Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
⁴ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Department of Genetics, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
⁶ Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
⁷ Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address: shwang@bsd.uchicago.edu.
⁸ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: virgin@wustl.edu.

Abstract

Autophagy is a lysosomal degradation pathway that is important in cellular homeostasis. Prior work showed a key role for the autophagy related 5 (Atg5) in resistance to Toxoplasma gondii. Here we show that the cassette of autophagy proteins involved in the conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, including Atg7, Atg3, and the Atg12-Atg5-Atg16L1 complex play crucial roles in the control of T. gondii in vitro and in vivo. In contrast, pharmacologic modulation of the degradative autophagy pathway or genetic deletion of other essential autophagy genes had no substantial effects. Rather the conjugation system was required for targeting of LC3 and interferon-γ effectors onto the vacuolar membrane of T. gondii and its consequent disruption. These data suggest that the ubiquitin-like conjugation systems that reorganize intracellular membranes during canonical autophagy are necessary for proper targeting of immune effectors to the intracellular vacuole membranes utilized by pathogens.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / immunology*
Autophagy-Related Protein 12
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Autophagy-Related Proteins
Carrier Proteins / immunology
HEK293 Cells
Humans
Interferon-gamma / immunology
Macrophages / immunology*
Mice
Mice, Knockout
Microtubule-Associated Proteins / chemistry
Microtubule-Associated Proteins / immunology
Phosphatidylethanolamines / chemistry
Protein Binding / immunology
Proteins / immunology
Toxoplasma / immunology*
Toxoplasmosis / immunology*
Toxoplasmosis / parasitology
Ubiquitin / metabolism
Ubiquitin-Conjugating Enzymes / immunology
Vacuoles / immunology
Vacuoles / metabolism
Vacuoles / parasitology

Substances

Atg12 protein, mouse
Atg16l1 protein, mouse
Atg5 protein, mouse
Atg7 protein, mouse
Autophagy-Related Protein 12
Autophagy-Related Protein 5
Autophagy-Related Proteins
Carrier Proteins
Map1lc3b protein, mouse
Microtubule-Associated Proteins
Phosphatidylethanolamines
Proteins
Ubiquitin
phosphatidylethanolamine
Interferon-gamma
Ubiquitin-Conjugating Enzymes
Autophagy-Related Protein 7
Atg3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding