The Listeriolysin O PEST-like Sequence Co-opts AP-2-Mediated Endocytosis to Prevent Plasma Membrane Damage during Listeria Infection

Chen Chen; Brittney N Nguyen; Gabriel Mitchell; Shally R Margolis; Darren Ma; Daniel A Portnoy

doi:10.1016/j.chom.2018.05.006

The Listeriolysin O PEST-like Sequence Co-opts AP-2-Mediated Endocytosis to Prevent Plasma Membrane Damage during Listeria Infection

Cell Host Microbe. 2018 Jun 13;23(6):786-795.e5. doi: 10.1016/j.chom.2018.05.006.

Authors

Chen Chen¹, Brittney N Nguyen², Gabriel Mitchell¹, Shally R Margolis¹, Darren Ma¹, Daniel A Portnoy³

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Graduate Group in Microbiology, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: portnoy@berkeley.edu.

Abstract

Listeriolysin O (LLO) is a cholesterol-dependent cytolysin that mediates escape of Listeria monocytogenes from a phagosome, enabling growth of the bacteria in the host cell cytosol. LLO contains a PEST-like sequence that prevents it from killing infected cells, but the mechanism involved is unknown. We found that the LLO PEST-like sequence was necessary to mediate removal of LLO from the interior face of the plasma membrane, where it coalesces into discrete puncta. LLO interacts with Ap2a2, an adaptor protein involved in endocytosis, via its PEST-like sequence, and Ap2a2-dependent endocytosis is required to prevent LLO-induced cytotoxicity. An unrelated PEST-like sequence from a human G protein-coupled receptor (GPCR), which also interacts with Ap2a2, could functionally complement the PEST-like sequence in L. monocytogenes LLO. These data revealed that LLO co-opts the host endocytosis machinery to protect the integrity of the host plasma membrane during L. monocytogenes infection.

Keywords: LLO; adaptor protein complex 2; ap2a2; bacteria; human calcium receptor; macrophage; membrane repair; pathogen.

Publication types

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

MeSH terms

Adaptor Protein Complex 2 / genetics
Adaptor Protein Complex 2 / metabolism*
Adaptor Protein Complex alpha Subunits / genetics
Adaptor Protein Complex alpha Subunits / metabolism*
Animals
Bacterial Toxins / metabolism*
Cell Membrane / metabolism*
Colony Count, Microbial
Cytosol / metabolism
Cytosol / microbiology
Disease Models, Animal
Endocytosis / physiology*
Female
Gene Knockdown Techniques
HEK293 Cells
HeLa Cells
Heat-Shock Proteins / metabolism*
Hemolysin Proteins / metabolism*
Host-Pathogen Interactions / physiology
Humans
Listeria monocytogenes / pathogenicity*
Listeriosis / metabolism*
Macrophages / microbiology
Mice
Mice, Inbred C57BL
Phagosomes / metabolism
Receptors, G-Protein-Coupled
Spleen / microbiology

Substances

Adaptor Protein Complex 2
Adaptor Protein Complex alpha Subunits
Bacterial Toxins
Heat-Shock Proteins
Hemolysin Proteins
Receptors, G-Protein-Coupled
adaptor protein complex 2, alpha 2 subunit
hlyA protein, Listeria monocytogenes

Abstract

Publication types

MeSH terms

Substances

Grants and funding