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Title: A Legionella Effector Disrupts Host Cytoskeletal Structure by Cleaving Actin

Legionella pneumophila, the etiological agent of Legionnaires' disease, replicates intracellularly in protozoan and human hosts. Successful colonization and replication of this pathogen in host cells requires the Dot/Icm type IVB secretion system, which translocates approximately 300 effector proteins into the host cell to modulate various cellular processes. In this study, we identified RavK as a Dot/Icm substrate that targets the host cytoskeleton and reduces actin filament abundance in mammalian cells upon ectopic expression. RavK harbors an H 95E XXH 99 motif associated with diverse metalloproteases, which is essential for the inhibition of yeast growth and for the induction of cell rounding in HEK293T cells. We demonstrate that the actin protein itself is the cellular target of RavK and that this effector cleaves actin at a site between residues Thr351 and Phe352. Importantly, RavK-mediated actin cleavage also occurs during L. pneumophila infection. Cleavage by RavK abolishes the ability of actin to form polymers. Furthermore, an F352A mutation renders actin resistant to RavK-mediated cleavage; expression of the mutant in mammalian cells suppresses the cell rounding phenotype caused by RavK, further establishing that actin is the physiological substrate of RavK. Furthermore, L. pneumophila exploits components of the host cytoskeleton by multiple effectors withmore » distinct mechanisms, highlighting the importance of modulating cellular processes governed by the actin cytoskeleton in the intracellular life cycle of this pathogen.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [1] ; ORCiD logo [1] ;  [5]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. UT Southwestern Medical Center, Dallas, TX (United States); Purdue Univ., West Lafayette, IN (United States)
  3. Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Purdue Univ., West Lafayette, IN (United States)
  4. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  5. Yale Univ. School of Medicine, New Haven, CT (United States)
Publication Date:
Report Number(s):
PNNL-SA-124050
Journal ID: ISSN 1553-7374; 453040220
Grant/Contract Number:
AC05-76RL01830
Type:
Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 13; Journal Issue: 1; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1372978