Bacteria–autophagy interplay: a battle for survival

Huang, Ju; Brumell, John H.

doi:10.1038/nrmicro3160

Cited by 480 publications

(476 citation statements)

References 157 publications

(178 reference statements)

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“…To determine whether compounds that inhibit replication of intracellular Salmonella affect its association with the antibacterial autophagy machinery, we measured the colocalization of dsRed-expressing Salmonella with both LC3 and NDP52, an adaptor protein that targets galectin-8-or Ub-coated Salmonella to autophagy (40). As reported previously, treatment with TFP enhanced the maximal colocalization of Salmonella and LC3 and NDP52 observed at 1 h p.i., which was maintained at later time points (4 h p.i.)…”

Section: Brd5631 Enhances Bacterial Clearance In An Autophagy-dependentmentioning

confidence: 88%

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Kuo

Castoreno

Aldrich

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production. BRD5631 can serve as a valuable tool for studying the role of autophagy in the context of cellular homeostasis and disease.high-throughput screening | autophagy | small-molecule probes | Crohn's disease

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Section: Brd5631 Enhances Bacterial Clearance In An Autophagy-dependentmentioning

confidence: 88%

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Kuo

Castoreno

Aldrich

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Formation of a double-membrane structure inside host cells, and the recruitment of ATG proteins and LC3B facilitates the establishment of mature autophagosomes which ultimately fuse with lysosomes to degrade the internal components, such as invading bacteria. However, some intracellular bacterial pathogens have evolved techniques to interfere with or take advantage of the autophagy machinery for intracellular survival [29]. Thus, investigating the interactions between pathogens and the autophagy pathway can provide novel insights into the molecular mechanisms required for successful autophagy.…”

Section: Discussionmentioning

confidence: 99%

Interaction between autophagic vesicles and the Coxiella-containing vacuole requires CLTC (clathrin heavy chain)

Latomanski

Newton

2018

Autophagy

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Coxiella burnetii is an intracellular bacterial pathogen which causes Q fever, a human infection with the ability to cause chronic disease with potentially life-threatening outcomes. In humans, Coxiella infects alveolar macrophages where it replicates to high numbers in a unique, pathogen-directed lysosome-derived vacuole. This compartment, termed the Coxiella-containing vacuole (CCV), has a low internal pH and contains markers both of lysosomes and autophagosomes. The CCV membrane is also enriched with CLTC (clathrin heavy chain) and this contributes to the success of the CCV. Here, we describe a role for CLTC, a scaffolding protein of clathrin-coated vesicles, in facilitating the fusion of autophagosomes with the CCV. During gene silencing of CLTC, CCVs are unable to fuse with each other, a phenotype also seen when silencing genes involved in macroautophagy/autophagy. MAP1LC3B/LC3B, which is normally observed inside the CCV, is excluded from CCVs in the absence of CLTC. Additionally, this study demonstrates that autophagosome fusion contributes to CCV size as cell starvation and subsequent autophagy induction leads to further CCV expansion. This is CLTC dependent, as the absence of CLTC renders autophagosomes no longer able to contribute to the expansion of the CCV. This investigation provides a functional link between CLTC and autophagy in the context of Coxiella infection and highlights the CCV as an important tool to explore the interactions between these vesicular trafficking pathways.

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“…Double-membrane vesicles called "autophagosomes" engulf nonfunctional or damaged cellular components and deliver them to lysosomes, where the content is degraded (11). Furthermore, it has been shown that autophagy acts as a cell-autonomous defense mechanism against intracellular bacteria, contributing to antibacterial immunity by regulating the inflammatory immune response and routing engulfed intracellular bacteria toward lysosomal degradation (12,13). Many pathogens are able to evade autophagy, although the molecular mechanisms at play remain largely uncharacterized (14)(15)(16)(17)(18)(19)(20).…”

Section: Significancementioning

confidence: 99%

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Rolando

Escoll

Nora

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

130

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Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, an intracellular pathogen that can cause a severe pneumonia in humans, is able to modulate autophagy through the action of effector proteins that are translocated into the host cell by the pathogen's Dot/Icm type IV secretion system. Many of these effectors share structural and sequence similarity with eukaryotic proteins. Indeed, phylogenetic analyses have indicated their acquisition by horizontal gene transfer from a eukaryotic host. Here we report that L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl was required for efficient infection of A/J mice, highlighting an important virulence role for this effector. Thus, we have uncovered a previously unidentified mechanism used by intracellular pathogens to inhibit autophagy, namely the disruption of host sphingolipid biosynthesis.Legionella pneumophila | sphingosine-1-phosphate lyase | autophagy | sphingolipids | virulence T he Gram-negative intracellular bacterium Legionella pneumophila is an opportunistic human pathogen responsible for Legionnaires' disease. The bacteria are naturally found in freshwater systems where they replicate within protozoan hosts (1). It is thought that the adaptation to replication within amoebas has equipped L. pneumophila with the factors required to replicate successfully within human macrophages following opportunistic infection (2). Through genome sequencing, we have discovered that L. pneumophila encodes a high number and variety of proteins similar in sequence to eukaryotic proteins that are never or rarely found in other prokaryotic genomes (3). Subsequent phylogenetic analyses have suggested that many of these proteins were acquired by horizontal gene transfer (3, 4). One of these proteins exhibits a high degree of similarity to eukaryotic sphingosine-1 phosphate lyase (SPL). The L. pneumophila SPL homolog (LpSpl encoded by gene lpp2128, lpg2176, or legS2) is conserved in all L. pneumophila strains sequenced to date, but absent from Legionella longbeachae (SI Appendix, Table S1). Phylogenetic analysis of SPL sequences showed that the L. pneumophila spl gene was most likely acquired early during evolution by horizontal gene transfer from a protozoan organism (4, 5). With the increase in genome sequences available...

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Bacteria–autophagy interplay: a battle for survival

Cited by 480 publications

References 157 publications

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Interaction between autophagic vesicles and the Coxiella-containing vacuole requires CLTC (clathrin heavy chain)

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

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