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Review
. 2019 Feb 27;83(2):e00058-18.
doi: 10.1128/MMBR.00058-18. Print 2019 May 15.

Taming the Triskelion: Bacterial Manipulation of Clathrin

Eleanor A Latomanski  1 , Hayley J Newton  2
Affiliations
Review

Taming the Triskelion: Bacterial Manipulation of Clathrin

Eleanor A Latomanski et al. Microbiol Mol Biol Rev. .

Abstract

The entry of pathogens into nonphagocytic host cells has received much attention in the past three decades, revealing a vast array of strategies employed by bacteria and viruses. A method of internalization that has been extensively studied in the context of viral infections is the use of the clathrin-mediated pathway. More recently, a role for clathrin in the entry of some intracellular bacterial pathogens was discovered. Classically, clathrin-mediated endocytosis was thought to accommodate internalization only of particles smaller than 150 nm; however, this was challenged upon the discovery that Listeria monocytogenes requires clathrin to enter eukaryotic cells. Now, with discoveries that clathrin is required during other stages of some bacterial infections, another paradigm shift is occurring. There is a more diverse impact of clathrin during infection than previously thought. Much of the recent data describing clathrin utilization in processes such as bacterial attachment, cell-to-cell spread and intracellular growth may be due to newly discovered divergent roles of clathrin in the cell. Not only does clathrin act to facilitate endocytosis from the plasma membrane, but it also participates in budding from endosomes and the Golgi apparatus and in mitosis. Here, the manipulation of clathrin processes by bacterial pathogens, including its traditional role during invasion and alternative ways in which clathrin supports bacterial infection, is discussed. Researching clathrin in the context of bacterial infections will reveal new insights that inform our understanding of host-pathogen interactions and allow researchers to fully appreciate the diverse roles of clathrin in the eukaryotic cell.

Keywords: Coxiella burnetii; EPEC; Listeria monocytogenes; Shigella flexneri; Staphylococcus aureus; adaptor proteins; autophagy; bacterial replication; clathrin; pathogen internalization.

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Figures

FIG 1
FIG 1
Clathrin-mediated endocytosis. (A) During initiation of clathrin-mediated endocytosis (CME), proteins FCHO2, intersectin 1, and EPS15 form an early-arriving complex at phospholipid-rich regions of the plasma membrane. (B) Cytoplasmic tails of cargo molecules are selectively bound by adaptor protein AP-2 or DAB2. Adaptors also bind phospholipids on membranes in order to recruit clathrin molecules. Clathrin begins to oligomerize into a lattice structure around the clathrin-coated pit. (C) Once the clathrin-coated vesicle has reached its optimal size, the vesicle is pinched from the membrane by dynamin. Dynamin is recruited by proteins including endophilin and sorting nexin 9. Actin plays an important part in movement of the newly formed vesicle. (D) Once the vesicle is detached from the membrane, the clathrin lattice is rapidly disassembled by Hsc70.
FIG 2
FIG 2
Clathrin and adaptor proteins throughout the cell. AP-1 (purple) is located at the trans-Golgi network and at intermediate (recycling) endosomes and mediates vesicle budding and movement of cargo between these two organelles. This process is dependent on clathrin. At the plasma membrane, AP-2 (red) facilitates clathrin-mediated endocytosis, with the resulting internalized vesicles trafficked throughout the cell. AP-3 (green) binds clathrin on early endosomes. AP-4 (orange) is utilized in a clathrin-independent manner at the trans-Golgi network, and AP-5 (blue) is found on late endosomes with no known clathrin interaction.
FIG 3
FIG 3
Site of Listeria monocytogenes entry into cells. A schematic of proteins involved in allowing L. monocytogenes uptake via the zipper mechanism is shown. The L. monocytogenes internalin proteins InlA and/or InlB engage the host proteins E-cadherin and Met, respectively, to begin recruitment of cellular components on the cytoplasmic side of the host cell. Clathrin is recruited to the site of entry and facilitates the eventual recruitment of F-actin through a signaling cascade that induces cytoskeletal rearrangements necessary for bacterial engulfment.
FIG 4
FIG 4
Bacterial pathogens coopt clathrin for nonendocytic functions. In order to establish close attachment to host cells, enteropathogenic Escherichia coli (EPEC) induces formation of actin-rich pedestals. Clathrin accumulates on the cytoplasmic side of the pedestal in an EPEC-induced manner and is required for subsequent actin recruitment and bacterial virulence. Coxiella burnetii replicates within a large Coxiella-containing vacuole (CCV) which is surrounded by clathrin. Clathrin is thought to be redirected to the CCV by effectors of the type IV secretion system (T4SS), CvpA and Cig57, that hijack clathrin-coated vesicles. Clathrin may also be delivered to the CCV when clathrin-associated autolysosomes fuse with the CCV through the activity of Cig2. Shigella flexneri is taken up into host cells by the trigger mechanism, a clathrin-independent mechanism which depends on the activity of the pathogen’s type III secretion system (T3SS). S. flexneri escapes into the cytosol and moves through the cell via actin-based motility until spreading to a neighboring cell at the tricellular junction. S. flexneri creates a protrusion which is engulfed by the neighboring cell using clathrin.
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