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PMID: 18996346 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens.

Cell host & microbe ·Vol. 4 ·No. 5 ·2008-11-13 ·Pages 458-69

Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, Cadwell K, Delgado MA, Ponpuak M, Green KG, Schmidt RE, Mizushima N, Deretic V, Sibley LD, Virgin HW

Abstract

The physiologic importance of autophagy proteins for control of mammalian bacterial and parasitic infection in vivo is unknown. Using mice with granulocyte- and macrophage-specific deletion of the essential autophagy protein Atg5, we show that Atg5 is required for in vivo resistance to the intracellular pathogens Listeria monocytogenes and Toxoplasma gondii. In primary macrophages, Atg5 was required for interferongamma (IFN-gamma)/LPS-induced damage to the T. gondii parasitophorous vacuole membrane and parasite clearance. While we did not detect classical hallmarks of autophagy, such as autophagosomes enveloping T. gondii, Atg5 was required for recruitment of IFN-gamma-inducible p47 GTPase IIGP1 (Irga6) to the vacuole membrane, an event that mediates IFN-gamma-mediated clearance of T. gondii. This work shows that Atg5 expression in phagocytic cells is essential for cellular immunity to intracellular pathogens in vivo, and that an autophagy protein can participate in immunity and intracellular killing of pathogens via autophagosome-independent processes such as GTPase trafficking.

MeSH Terms
Animals Autophagy Autophagy-Related Protein 5 Cells, Cultured Host-Pathogen Interactions Humans Immunity, Cellular Interferon-gamma/immunology Listeria monocytogenes/physiology Listeriosis/immunology,microbiology Lysosomes/immunology,parasitology Macrophages/immunology,parasitology Mice Mice, Inbred CBA Mice, Knockout Microtubule-Associated Proteins/genetics,immunology Signal Transduction Toxoplasma/physiology Toxoplasmosis/immunology,parasitology
Chemicals
Atg5 protein, mouse Autophagy-Related Protein 5 Microtubule-Associated Proteins Interferon-gamma
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Zhao Zijiang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Fux Blima
Goodwin Megan
Dunay Ildiko R
Strong David
Miller Brian C
Cadwell Ken
Delgado Monica A
Ponpuak Marisa
Green Karen G
Schmidt Robert E
Mizushima Noboru
Deretic Vojo
Sibley L David
Virgin Herbert W
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Article Info
Journal
Cell host & microbe
Abbr.
Cell Host Microbe
ISSN
1934-6069
DOI
10.1016/j.chom.2008.10.003
Published
2008-11-13
Pages
458-69
Language
English
Region
United States
NLM ID
101302316
PMCID
PMC2682425
Subset
IM
Grants
NIAID NIH HHS · R01 AI036629 · United States
NIAID NIH HHS · R01 AI042999 · United States
NIAID NIH HHS · AI071299 · United States
NIAID NIH HHS · U54 AI057160-010005 · United States
NIAID NIH HHS · R01 AI069345 · United States
NIAID NIH HHS · R37 AI042999 · United States
NIAID NIH HHS · AI036629 · United States
NIAID NIH HHS · U54 AI057160 · United States
NIAID NIH HHS · R21 AI071299 · United States
NIAID NIH HHS · R21 AI071299-02 · United States
NIAID NIH HHS · AI069345 · United States
NIAID NIH HHS · R01 AI036629-15 · United States
Corrections
CommentIn
PMID: 18996340
External Links
PubMed source DOI: 10.1016/j.chom.2008.10.003 PMC Full Text View journal details
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