The Legionella Effector RavZ Inhibits Host Autophagy Through Irreversible Atg8 Deconjugation
Open accessAbstract
Eukaryotic cells can use the autophagy pathway to defend against microbes that gain access to the cytosol or reside in pathogen-modified vacuoles. It remains unclear if pathogens have evolved specific mechanisms to manipulate autophagy. Here, we found that the intracellular pathogen Legionella pneumophila could interfere with autophagy by using the bacterial effector protein RavZ to directly uncouple Atg8 proteins attached to phosphatidylethanolamine on autophagosome membranes. RavZ hydrolyzed the amide bond between the carboxyl-terminal glycine residue and an adjacent aromatic residue in Atg8 proteins, producing an Atg8 protein that could not be reconjugated by Atg7 and Atg3. Thus, intracellular pathogens can inhibit autophagy by irreversibly inactivating Atg8 proteins during infection.
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Lipidation of LC3-family proteins is required for recycling of TLR4, TREM2, and CD36.
“The requirement for ATG4, which converts LC3 to LC3-I (Kabeya et al., 2004) and the effect of RavZ, which irreversibly cleaves lipidated LC3 (Choy et al., 2012; Kwon et al., 2017), strongly suggest that lipidation of LC3-family proteins is required for recycling of these receptors.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Choy et al., 2012
RavZ prevented receptor recycling.
“The Legionella-derived protease, RavZ, which irreversibly cleaves lipidated LC3 (Choy et al., 2012; Kwon et al., 2017) also prevented this receptor recycling, again, as defined by this method (Lucin et al., 2013; Yin et al., 2016).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Choy et al., 2012
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Self-citation
- Authors
- Choy, A., Dancourt, J., Mugo, B., O’Connor, T. J., Isberg, R. R., Melia, T. J., & Roy, C. R.
- Affiliations
- Yale University (US)
- Tufts University (US)
- Corresponding author
- Melia, Thomas J.
- Roy, Craig R.
- Venue
- Science
- Published
- 2012-11-23
- Volume
- 338
- Issue
- 6110
- Pages
- 1072-1076
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3682818
- OpenAlex
- W1966771851
- Cited by
- 473
- References
- 28
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 24 · 2023: 30 · 2022: 30 · 2021: 46 · 2020: 42 · 2019: 52 · 2018: 31 · 2017: 43 · 2016: 41 · 2015: 30 · 2014: 21 · 2013: 34 · 2012: 2
- FWCI
- 20.76
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases (AI041699, R01AI041699, R37AI041699, AI048770, R29AI041699, R01AI048770, AI007019, T32AI007019)
- National Institute of Neurological Disorders and Stroke (NS063973, R01NS063973)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Legionella pneumophila, autophagy inhibition, ATG7, ATG3, phosphatidylethanolamine, bacterial effector proteins, host-pathogen interaction, intracellular pathogens
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein 8 Family, Autophagy-Related Protein 7, Autophagy, Bacterial Proteins, Glycine, Humans, Hydrolysis, Legionnaires' Disease, Microfilament Proteins, Phagosomes, Legionella pneumophila, Gene Deletion, Cell Culture Techniques, Ubiquitin-Conjugating Enzymes, Ubiquitin-Activating Enzymes, Adaptor Proteins, Signal Transducing, Host-Pathogen Interactions, Cysteine Proteases, HEK293 Cells
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