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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Inst. Pasteur, Paris (France); CNRS UMR 3525, Paris (France)
  2. Inst. Necker Enfants-Malades, Paris (France); Univ. Paris Descartes-Sorbonne Paris Cité, Paris (France)
  3. Centre de Recherches en Cancérologie de Toulouse (France); Inst. of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona (Spain)
  4. Univ. of Toronto, ON (Canada); Hospital for Sick Children, Toronto, ON (Canada)
  5. Monash Univ., Melbourne, VIC (Australia)
  6. Univ. of Toronto, ON (Canada)
  7. Univ. of Zurich (Switzerland)
  8. Univ. of Melbourne (Australia)
  9. Univ. of Melbourne at the Peter Doherty Inst. for Infection and Immunity, Melbourne, VIC (Australia)
  10. Centre de Recherches en Cancérologie de Toulouse (France)
  11. Monash Univ., Clayton, VIC (Australia)
+ Show Author Affiliations

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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Swiss National Science Foundation (SNSF)
Grant/Contract Number:
ANR-10-LABX-62-IBEID; ANR-13-IFEC-0003-02; GM074942; GM094585; AC02-06CH11357
OSTI ID:
1239413
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 7; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 101 works
Citation information provided by
Web of Science

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Cited By (33)

Autophagy—from molecular mechanisms to clinical relevance journal December 2016
Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain journal July 2017
Legionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17 journal May 2017
Legionella and Coxiella effectors: strength in diversity and activity journal July 2017
Mitochondria-associated membranes (MAMs) and inflammation journal February 2018
Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes journal May 2018
Intracellular parasitism, the driving force of evolution of Legionella pneumophila and the genus Legionella journal May 2019
More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells journal January 2019
Interaction between autophagic vesicles and the Coxiella -containing vacuole requires CLTC (clathrin heavy chain) journal July 2018
Bacterial interaction with host autophagy journal January 2019
Tiny architects: biogenesis of intracellular replicative niches by bacterial pathogens journal March 2018
Evasion of phagotrophic predation by protist hosts and innate immunity of metazoan hosts by Legionella pneumophila journal October 2018
Loss of alkaline ceramidase inhibits autophagy in Arabidopsis and plays an important role during environmental stress response: Link between sphingolipids and autophagy journal February 2018
The Life Cycle of L. pneumophila: Cellular Differentiation Is Linked to Virulence and Metabolism journal January 2018
Acanthamoeba and Dictyostelium as Cellular Models for Legionella Infection journal March 2018
How Viral and Intracellular Bacterial Pathogens Reprogram the Metabolism of Host Cells to Allow Their Intracellular Replication journal March 2019
Macrophage Autophagy and Bacterial Infections journal November 2017
Amino Acids As Mediators of Metabolic Cross Talk between Host and Pathogen journal February 2018
Autophagy and Its Interaction With Intracellular Bacterial Pathogens journal May 2018
Bacterial Manipulation of Autophagic Responses in Infection and Inflammation journal December 2019
Intracellular parasitism, the driving force of evolution of Legionella pneumophila and the genus Legionella journal June 2019
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More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells. text January 2019
Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages journal September 2017
Bacterial secretion system skews the fate of Legionella-containing vacuoles towards LC3-associated phagocytosis journal March 2017
How to rewire the host cell: A home improvement guide for intracellular bacteria journal November 2017
A Unique cis -Encoded Small Noncoding RNA Is Regulating Legionella pneumophila Hfq Expression in a Life Cycle-Dependent Manner journal March 2017
S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling journal January 2017
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Intravascular Schistosoma mansoni Cleave the Host Immune and Hemostatic Signaling Molecule Sphingosine-1-Phosphate via Tegumental Alkaline Phosphatase journal July 2018

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59 BASIC BIOLOGICAL SCIENCES
Legionella pneumophila
sphingosine-1-phosphate lyase
autophagy
sphingolipids
virulence