Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity

Shivani Agarwal; Hyunjin Kim; Robin B. Chan; Shivangi Agarwal; Rebecca Williamson; Wonhwa Cho; Gilbert D. Paolo; Karla J.F. Satchell

doi:10.1038/ncomms9745

Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity

Shivani Agarwal, Hyunjin Kim, Robin B. Chan, Shivangi Agarwal, Rebecca Williamson, Wonhwa Cho, Gilbert D. Paolo, Karla J.F. Satchell^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

Vibrio cholerae, responsible for acute gastroenteritis secretes a large multifunctional-autoprocessing repeat-in-toxin (MARTX) toxin linked to evasion of host immune system, facilitating colonization of small intestine. Unlike other effector domains of the multifunctional toxin that target cytoskeleton, the function of alpha-beta hydrolase (ABH) remained elusive. This study demonstrates that ABH is an esterase/lipase with catalytic Ser-His-Asp triad. ABH binds with high affinity to phosphatidylinositol-3-phosphate (PtdIns3P) and cleaves the fatty acid in PtdIns3P at the sn1 position in vitro making it the first PtdIns3P-specific phospholipase A1 (PLA1). Expression of ABH in vivo reduces intracellular PtdIns3P levels and its PtdIns3P-specific PLA1 activity blocks endosomal and autophagic pathways. In accordance with recent studies acknowledging the potential of extracellular pathogens to evade or exploit autophagy to prevent their clearance and facilitate survival, this is the first report highlighting the role of ABH in inhibiting autophagy and endosomal trafficking induced by extracellular V. cholerae.

Original language	English (US)
Article number	8745
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9745
State	Published - Oct 26 2015

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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title = "Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity",

abstract = "Vibrio cholerae, responsible for acute gastroenteritis secretes a large multifunctional-autoprocessing repeat-in-toxin (MARTX) toxin linked to evasion of host immune system, facilitating colonization of small intestine. Unlike other effector domains of the multifunctional toxin that target cytoskeleton, the function of alpha-beta hydrolase (ABH) remained elusive. This study demonstrates that ABH is an esterase/lipase with catalytic Ser-His-Asp triad. ABH binds with high affinity to phosphatidylinositol-3-phosphate (PtdIns3P) and cleaves the fatty acid in PtdIns3P at the sn1 position in vitro making it the first PtdIns3P-specific phospholipase A1 (PLA1). Expression of ABH in vivo reduces intracellular PtdIns3P levels and its PtdIns3P-specific PLA1 activity blocks endosomal and autophagic pathways. In accordance with recent studies acknowledging the potential of extracellular pathogens to evade or exploit autophagy to prevent their clearance and facilitate survival, this is the first report highlighting the role of ABH in inhibiting autophagy and endosomal trafficking induced by extracellular V. cholerae.",

author = "Shivani Agarwal and Hyunjin Kim and Chan, {Robin B.} and Shivangi Agarwal and Rebecca Williamson and Wonhwa Cho and Paolo, {Gilbert D.} and Satchell, {Karla J.F.}",

note = "Funding Information: We thank Harald Stenmark, University of Oslo, Norway for providing 2 ⨯ -FYVEHRS-GFP plasmid, Sharon Tooze, Cancer Research, UK, for WIPI-1-GFP plasmid, J. Gruenberg, Geneva, Switzerland for Rab5Q79L plasmid, Martina Egerer for pME14 plasmid, Brett Giessler and Marco Biancucci for advice and Kevin Ziolo and Jazel Dolores for technical support. Core services were provided by Northwestern University Genomics Core, Center for Advanced Microscopy (NCI CCSG P30 CA060553) and Keck Biophysics Core. This work was supported by an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund and by NIH R01 grants AI051490, AI092825 and AI098369 (to KJFS), NS056049 (to GDP), and GM68849 (to WC). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = oct,

day = "26",

doi = "10.1038/ncomms9745",

language = "English (US)",

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journal = "Nature communications",

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AU - Agarwal, Shivani

AU - Kim, Hyunjin

AU - Chan, Robin B.

AU - Agarwal, Shivangi

AU - Williamson, Rebecca

AU - Cho, Wonhwa

AU - Paolo, Gilbert D.

AU - Satchell, Karla J.F.

N1 - Funding Information: We thank Harald Stenmark, University of Oslo, Norway for providing 2 ⨯ -FYVEHRS-GFP plasmid, Sharon Tooze, Cancer Research, UK, for WIPI-1-GFP plasmid, J. Gruenberg, Geneva, Switzerland for Rab5Q79L plasmid, Martina Egerer for pME14 plasmid, Brett Giessler and Marco Biancucci for advice and Kevin Ziolo and Jazel Dolores for technical support. Core services were provided by Northwestern University Genomics Core, Center for Advanced Microscopy (NCI CCSG P30 CA060553) and Keck Biophysics Core. This work was supported by an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund and by NIH R01 grants AI051490, AI092825 and AI098369 (to KJFS), NS056049 (to GDP), and GM68849 (to WC). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/10/26

Y1 - 2015/10/26

N2 - Vibrio cholerae, responsible for acute gastroenteritis secretes a large multifunctional-autoprocessing repeat-in-toxin (MARTX) toxin linked to evasion of host immune system, facilitating colonization of small intestine. Unlike other effector domains of the multifunctional toxin that target cytoskeleton, the function of alpha-beta hydrolase (ABH) remained elusive. This study demonstrates that ABH is an esterase/lipase with catalytic Ser-His-Asp triad. ABH binds with high affinity to phosphatidylinositol-3-phosphate (PtdIns3P) and cleaves the fatty acid in PtdIns3P at the sn1 position in vitro making it the first PtdIns3P-specific phospholipase A1 (PLA1). Expression of ABH in vivo reduces intracellular PtdIns3P levels and its PtdIns3P-specific PLA1 activity blocks endosomal and autophagic pathways. In accordance with recent studies acknowledging the potential of extracellular pathogens to evade or exploit autophagy to prevent their clearance and facilitate survival, this is the first report highlighting the role of ABH in inhibiting autophagy and endosomal trafficking induced by extracellular V. cholerae.

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JF - Nature communications

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Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity

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