The Autophagy Receptor TAX1BP1 and the Molecular Motor Myosin VI Are Required for Clearance of Salmonella Typhimurium by Autophagy
Identifieur interne : 000087 ( Pmc/Curation ); précédent : 000086; suivant : 000088The Autophagy Receptor TAX1BP1 and the Molecular Motor Myosin VI Are Required for Clearance of Salmonella Typhimurium by Autophagy
Auteurs : David A. Tumbarello [Royaume-Uni] ; Paul T. Manna [Royaume-Uni] ; Mark Allen [Royaume-Uni] ; Mark Bycroft [Royaume-Uni] ; Susan D. Arden [Royaume-Uni] ; John Kendrick-Jones [Royaume-Uni] ; Folma Buss [Royaume-Uni]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2015.
Abstract
Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria. Our structural studies demonstrate that the ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site and point mutations in the TAX1BP1 zinc finger domains that affect ubiquitin binding also ablate binding to myosin VI. This mutually exclusive binding and the association of TAX1BP1 with LC3 on the outer limiting membrane of autophagosomes may suggest a molecular mechanism for recruitment of this motor to autophagosomes. The predominant role of TAX1BP1, a paralogue of NDP52, in xenophagy is supported by our evolutionary analysis, which demonstrates that functionally intact NDP52 is missing in Xenopus and mice, whereas TAX1BP1 is expressed in all vertebrates analysed. In summary, this work highlights the importance of TAX1BP1 as a novel autophagy receptor in myosin VI-mediated xenophagy. Our study identifies essential new machinery for the autophagy-dependent clearance of Salmonella typhimurium and suggests modulation of myosin VI motor activity as a potential therapeutic target in cellular immunity.
Url:
DOI: 10.1371/journal.ppat.1005174
PubMed: 26451915
PubMed Central: 4599966
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<front><div type="abstract" xml:lang="en"><p>Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria. Our structural studies demonstrate that the ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site and point mutations in the TAX1BP1 zinc finger domains that affect ubiquitin binding also ablate binding to myosin VI. This mutually exclusive binding and the association of TAX1BP1 with LC3 on the outer limiting membrane of autophagosomes may suggest a molecular mechanism for recruitment of this motor to autophagosomes. The predominant role of TAX1BP1, a paralogue of NDP52, in xenophagy is supported by our evolutionary analysis, which demonstrates that functionally intact NDP52 is missing in Xenopus and mice, whereas TAX1BP1 is expressed in all vertebrates analysed. In summary, this work highlights the importance of TAX1BP1 as a novel autophagy receptor in myosin VI-mediated xenophagy. Our study identifies essential new machinery for the autophagy-dependent clearance of Salmonella typhimurium and suggests modulation of myosin VI motor activity as a potential therapeutic target in cellular immunity.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26451915</article-id>
<article-id pub-id-type="pmc">4599966</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1005174</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-15-00796</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The Autophagy Receptor TAX1BP1 and the Molecular Motor Myosin VI Are Required for Clearance of Salmonella Typhimurium by Autophagy</article-title>
<alt-title alt-title-type="running-head">TAX1BP1 and Myosin VI Function in Antibacterial Autophagy</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tumbarello</surname>
<given-names>David A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="currentaff001"><sup>¤</sup>
</xref>
<xref rid="cor001" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Manna</surname>
<given-names>Paul T.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Allen</surname>
<given-names>Mark</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bycroft</surname>
<given-names>Mark</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arden</surname>
<given-names>Susan D.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kendrick-Jones</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Buss</surname>
<given-names>Folma</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref rid="cor001" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>MRC Laboratory of Molecular Biology, Cambridge, United Kingdom</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Luo</surname>
<given-names>Zhao-Qing</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Purdue University, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="conflict" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: DAT JKJ FB. Performed the experiments: DAT PTM MA MB JKJ SDA FB. Analyzed the data: DAT PTM MA MB JKJ SDA FB. Wrote the paper: DAT FB PTM JKJ.</p>
</fn>
<fn fn-type="current-aff" id="currentaff001"><label>¤</label>
<p>Current address: Centre for Biological Sciences, Life Science Building 85, University of Southampton, Highfield Campus, Southampton, United Kingdom</p>
</fn>
<corresp id="cor001">* E-mail: <email>D.A.Tumbarello@soton.ac.uk</email>
(DAT); <email>fb207@cam.ac.uk</email>
(FB)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>9</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>10</month>
<year>2015</year>
</pub-date>
<volume>11</volume>
<issue>10</issue>
<elocation-id>e1005174</elocation-id>
<history><date date-type="received"><day>2</day>
<month>4</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>28</day>
<month>8</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-year>2015</copyright-year>
<copyright-holder>Tumbarello et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="ppat.1005174.pdf"></self-uri>
<abstract><p>Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria. Our structural studies demonstrate that the ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site and point mutations in the TAX1BP1 zinc finger domains that affect ubiquitin binding also ablate binding to myosin VI. This mutually exclusive binding and the association of TAX1BP1 with LC3 on the outer limiting membrane of autophagosomes may suggest a molecular mechanism for recruitment of this motor to autophagosomes. The predominant role of TAX1BP1, a paralogue of NDP52, in xenophagy is supported by our evolutionary analysis, which demonstrates that functionally intact NDP52 is missing in Xenopus and mice, whereas TAX1BP1 is expressed in all vertebrates analysed. In summary, this work highlights the importance of TAX1BP1 as a novel autophagy receptor in myosin VI-mediated xenophagy. Our study identifies essential new machinery for the autophagy-dependent clearance of Salmonella typhimurium and suggests modulation of myosin VI motor activity as a potential therapeutic target in cellular immunity.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>One of the most common causes of food poisoning is the pathogen <italic>Salmonella enterica</italic>
serovar Typhimurium. This pathogen enters the cells of the body through the intestine and after invasion of these cells it survives and multiplies due to its own ability to evade the immune system, thus causing infection. Understanding how this pathogen evades the natural protective mechanisms present within the cell that normally degrade a foreign body is an important area of current research. Here, we describe a process by which the control of infection is mediated by a cellular self-degradation pathway called autophagy. This pathway requires specific adaptor proteins within the cell that identify the foreign pathogen and target it for degradation. We define the function of a specific adaptor protein required for this process of pathogen recognition and show how this adaptor links to and utilises other cellular machinery, the actin cytoskeleton and associated motor proteins to accomplish this function and restrict pathogen proliferation. Our work thus demonstrates that this specialised autophagy pathway requires the coordination of multiple proteins and we identify novel machinery that is essential to efficiently degrade Salmonella Typhimurium within cells.</p>
</abstract>
<funding-group><funding-statement>FB and DAT thank the Wellcome Trust (<ext-link ext-link-type="uri" xlink:href="http://www.wellcome.ac.uk">www.wellcome.ac.uk</ext-link>
) for funding of a University Award to FB (086743), the CIMR Strategic Award (100140) and an equipment grant [093026]. FB also thanks the Medical Research Council UK (<ext-link ext-link-type="uri" xlink:href="http://www.mrc.ac.uk">www.mrc.ac.uk</ext-link>
) for funding of a project grant (MR/K000888/1). JKJ, MA and MB were supported by the Medical Research Council UK (<ext-link ext-link-type="uri" xlink:href="http://www.mrc.ac.uk">www.mrc.ac.uk</ext-link>
) (U105184325). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="8"></fig-count>
<table-count count="0"></table-count>
<page-count count="26"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The coordinates and the NMR restraints have been deposited in the PDB with the codes PDB: 5aas and r5aasmr, respectively. All other data is in the paper.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The coordinates and the NMR restraints have been deposited in the PDB with the codes PDB: 5aas and r5aasmr, respectively. All other data is in the paper.</p>
</notes>
</front>
</pmc>
</record>
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