Merkel Cell Polyomavirus DNA Replication Induces Senescence in Human Dermal Fibroblasts in a Kap1/Trim28-Dependent Manner
Identifieur interne : 000106 ( Pmc/Checkpoint ); précédent : 000105; suivant : 000107Merkel Cell Polyomavirus DNA Replication Induces Senescence in Human Dermal Fibroblasts in a Kap1/Trim28-Dependent Manner
Auteurs : Svenja Siebels [Allemagne] ; Manja Czech-Sioli [Allemagne] ; Michael Spohn [Allemagne] ; Claudia Schmidt [Allemagne] ; Juliane Theiss [Allemagne] ; Daniela Indenbirken [Allemagne] ; Thomas Günther [Allemagne] ; Adam Grundhoff [Allemagne] ; Nicole Fischer [Allemagne]Source :
- mBio [ 2150-7511 ] ; 2020.
Abstract
We here describe Kap1 as a restriction factor in MCPyV infection. We report a novel, indirect mechanism by which Kap1 affects MCPyV replication. In contrast with from other DNA viruses, Kap1 does not associate with the viral genome in MCPyV infection and has no impact on viral gene expression. In MCPyV-infected nHDF cells, Kap1 phosphorylation (pKap1 S824) accumulates because of genomic stress mainly induced by viral DNA replication. In contrast, ectopic expression of LT or LT MCPyV mutants, previously shown to be important for induction of genotoxic stress, does not result in a similar extent of pKap1 accumulation. We show that cells actively replicating MCPyV accumulate pKap1 (in a manner dependent on the presence of ATM) and display a senescence phenotype reflected by G2 arrest. These results are supported by transcriptome analyses showing that LT antigen, in a manner dependent on the presence of Kap1, induces expression of secreted factors, which is known as the senescence-associated secretory phenotype (SASP).
Url:
DOI: 10.1128/mBio.00142-20
PubMed: 32156811
PubMed Central: 7064754
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>We here describe Kap1 as a restriction factor in MCPyV infection. We report a novel, indirect mechanism by which Kap1 affects MCPyV replication. In contrast with from other DNA viruses, Kap1 does not associate with the viral genome in MCPyV infection and has no impact on viral gene expression. In MCPyV-infected nHDF cells, Kap1 phosphorylation (pKap1 S824) accumulates because of genomic stress mainly induced by viral DNA replication. In contrast, ectopic expression of LT or LT MCPyV mutants, previously shown to be important for induction of genotoxic stress, does not result in a similar extent of pKap1 accumulation. We show that cells actively replicating MCPyV accumulate pKap1 (in a manner dependent on the presence of ATM) and display a senescence phenotype reflected by G<sub>2</sub>
arrest. These results are supported by transcriptome analyses showing that LT antigen, in a manner dependent on the presence of Kap1, induces expression of secreted factors, which is known as the senescence-associated secretory phenotype (SASP).</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">mBio</journal-id>
<journal-id journal-id-type="iso-abbrev">mBio</journal-id>
<journal-id journal-id-type="hwp">mbio</journal-id>
<journal-id journal-id-type="pmc">mbio</journal-id>
<journal-id journal-id-type="publisher-id">mBio</journal-id>
<journal-title-group><journal-title>mBio</journal-title>
</journal-title-group>
<issn pub-type="epub">2150-7511</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32156811</article-id>
<article-id pub-id-type="pmc">7064754</article-id>
<article-id pub-id-type="publisher-id">mBio00142-20</article-id>
<article-id pub-id-type="doi">10.1128/mBio.00142-20</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="overline"><subject>Host-Microbe Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Merkel Cell Polyomavirus DNA Replication Induces Senescence in Human Dermal Fibroblasts in a Kap1/Trim28-Dependent Manner</article-title>
<alt-title alt-title-type="running-head">Kap1 Restricts MCPyV DNA Replication</alt-title>
<alt-title alt-title-type="short-authors">Siebels et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Siebels</surname>
<given-names>Svenja</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Czech-Sioli</surname>
<given-names>Manja</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spohn</surname>
<given-names>Michael</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schmidt</surname>
<given-names>Claudia</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Theiss</surname>
<given-names>Juliane</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Indenbirken</surname>
<given-names>Daniela</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Günther</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grundhoff</surname>
<given-names>Adam</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Fischer</surname>
<given-names>Nicole</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<aff id="aff1"><label>a</label>
<addr-line>Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line>
</aff>
<aff id="aff2"><label>b</label>
<addr-line>Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany</addr-line>
</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Imperiale</surname>
<given-names>Michael J.</given-names>
</name>
<role>Editor</role>
<aff>University of Michigan—Ann Arbor</aff>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Nicole Fischer, <email>nfischer@uke.de</email>
.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>10</day>
<month>3</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><season>Mar-Apr</season>
<year>2020</year>
</pub-date>
<volume>11</volume>
<issue>2</issue>
<elocation-id>e00142-20</elocation-id>
<history><date date-type="received"><day>21</day>
<month>1</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>29</day>
<month>1</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2020 Siebels et al.</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>Siebels et al.</copyright-holder>
<license license-type="open-access" xlink:href="https://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="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>
.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="mBio.00142-20.pdf"></self-uri>
<abstract abstract-type="precis"><p>We here describe Kap1 as a restriction factor in MCPyV infection. We report a novel, indirect mechanism by which Kap1 affects MCPyV replication. In contrast with from other DNA viruses, Kap1 does not associate with the viral genome in MCPyV infection and has no impact on viral gene expression. In MCPyV-infected nHDF cells, Kap1 phosphorylation (pKap1 S824) accumulates because of genomic stress mainly induced by viral DNA replication. In contrast, ectopic expression of LT or LT MCPyV mutants, previously shown to be important for induction of genotoxic stress, does not result in a similar extent of pKap1 accumulation. We show that cells actively replicating MCPyV accumulate pKap1 (in a manner dependent on the presence of ATM) and display a senescence phenotype reflected by G<sub>2</sub>
arrest. These results are supported by transcriptome analyses showing that LT antigen, in a manner dependent on the presence of Kap1, induces expression of secreted factors, which is known as the senescence-associated secretory phenotype (SASP).</p>
</abstract>
<abstract><title>ABSTRACT</title>
<p>Merkel cell polyomavirus (MCPyV) is the only polyomavirus known to be associated with tumorigenesis in humans. Similarly to other polyomaviruses, MCPyV expresses a <underline>l</underline>
arge <underline>t</underline>
umor antigen (LT-Ag) that, together with a <underline>s</underline>
mall <underline>t</underline>
umor antigen (sT-Ag), contributes to cellular transformation and that is of critical importance for the initiation of the viral DNA replication. Understanding the cellular protein network regulated by MCPyV early proteins will significantly contribute to our understanding of the natural MCPyV life cycle as well as of the mechanisms by which the virus contributes to cellular transformation. We here describe KRAB-associated protein 1 (Kap1), a chromatin remodeling factor involved in cotranscriptional regulation, as a novel protein interaction partner of MCPyV T antigens sT and LT. Kap1 knockout results in a significant increase in the level of viral DNA replication that is highly suggestive of Kap1 being an important host restriction factor during MCPyV infection. Differently from other DNA viruses, MCPyV gene expression is unaffected in the absence of Kap1 and Kap1 does not associate with the viral genome. Instead, we show that in primary normal human dermal fibroblast (nHDF) cells, MCPyV DNA replication, but not T antigen expression alone, induces ataxia telangiectasia mutated (ATM) kinase-dependent Kap1 S824 phosphorylation, a mechanism that typically facilitates repair of double-strand breaks in heterochromatin by arresting the cells in G<sub>2</sub>
. We show that MCPyV-induced inhibition of cell proliferation is mainly conferred by residues within the origin binding domain and thereby by viral DNA replication. Our data suggest that phosphorylation of Kap1 and subsequent Kap1-dependent G<sub>2</sub>
arrest/senescence represent host defense mechanisms against MCPyV replication in nHDF cells.</p>
</abstract>
<kwd-group><title>KEYWORDS</title>
<kwd>Kap1/Trim28</kwd>
<kwd>Merkel cell polyomavirus</kwd>
<kwd>senescence</kwd>
<kwd>viral DNA replication</kwd>
<kwd>viral restriction factor</kwd>
</kwd-group>
<funding-group><award-group id="award1"><funding-source><institution-wrap><institution>Behörde für Wissenschaft, Forschung und Gleichstellung, Landesforschungsförderung Hamburg</institution>
</institution-wrap>
</funding-source>
<award-id>EPILOG</award-id>
<principal-award-recipient><name><surname>Grundhoff</surname>
<given-names>Adam</given-names>
</name>
</principal-award-recipient>
<principal-award-recipient><name><surname>Fischer</surname>
<given-names>Nicole</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award2"><funding-source><institution-wrap><institution>Erich und Gertrud Roggenbuck-Stiftung (Erich and Gertrud Roggenbuck Foundation)</institution>
<institution-id>https://doi.org/10.13039/100010124</institution-id>
</institution-wrap>
</funding-source>
<principal-award-recipient><name><surname>Fischer</surname>
<given-names>Nicole</given-names>
</name>
</principal-award-recipient>
<principal-award-recipient><name><surname>Siebels</surname>
<given-names>Svenja</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<counts><count count="10" count-type="supplementary-material"></count>
<fig-count count="12"></fig-count>
<table-count count="0"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="63"></ref-count>
<page-count count="22"></page-count>
<word-count count="12493"></word-count>
</counts>
<custom-meta-group><custom-meta><meta-name>cover-date</meta-name>
<meta-value>March/April 2020</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Allemagne</li>
</country>
<region><li>Hambourg</li>
</region>
<settlement><li>Hambourg</li>
</settlement>
</list>
<tree><country name="Allemagne"><region name="Hambourg"><name sortKey="Siebels, Svenja" sort="Siebels, Svenja" uniqKey="Siebels S" first="Svenja" last="Siebels">Svenja Siebels</name>
</region>
<name sortKey="Czech Sioli, Manja" sort="Czech Sioli, Manja" uniqKey="Czech Sioli M" first="Manja" last="Czech-Sioli">Manja Czech-Sioli</name>
<name sortKey="Fischer, Nicole" sort="Fischer, Nicole" uniqKey="Fischer N" first="Nicole" last="Fischer">Nicole Fischer</name>
<name sortKey="Grundhoff, Adam" sort="Grundhoff, Adam" uniqKey="Grundhoff A" first="Adam" last="Grundhoff">Adam Grundhoff</name>
<name sortKey="Gunther, Thomas" sort="Gunther, Thomas" uniqKey="Gunther T" first="Thomas" last="Günther">Thomas Günther</name>
<name sortKey="Indenbirken, Daniela" sort="Indenbirken, Daniela" uniqKey="Indenbirken D" first="Daniela" last="Indenbirken">Daniela Indenbirken</name>
<name sortKey="Schmidt, Claudia" sort="Schmidt, Claudia" uniqKey="Schmidt C" first="Claudia" last="Schmidt">Claudia Schmidt</name>
<name sortKey="Spohn, Michael" sort="Spohn, Michael" uniqKey="Spohn M" first="Michael" last="Spohn">Michael Spohn</name>
<name sortKey="Theiss, Juliane" sort="Theiss, Juliane" uniqKey="Theiss J" first="Juliane" last="Theiss">Juliane Theiss</name>
<name sortKey="Theiss, Juliane" sort="Theiss, Juliane" uniqKey="Theiss J" first="Juliane" last="Theiss">Juliane Theiss</name>
</country>
</tree>
</affiliations>
</record>
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