SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity
SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increase...
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| Veröffentlicht in: | PLoS pathogens 2020-09, Vol.16 (9), p.e1008855-e1008855 |
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| creator | De Meo, Simone Dell'Oste, Valentina Molfetta, Rosa Tassinari, Valentina Lotti, Lavinia Vittoria Vespa, Simone Pignoloni, Benedetta Covino, Daniela Angela Fantuzzi, Laura Bona, Roberta Zingoni, Alessandra Nardone, Ilaria Biolatti, Matteo Coscia, Alessandra Paolini, Rossella Benkirane, Monsef Edfors, Fredrik Sandalova, Tatyana Achour, Adnane Hiscott, John Landolfo, Santo Santoni, Angela Cerboni, Cristina |
| description | SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities. |
| doi_str_mv | 10.1371/journal.ppat.1008855 |
| format | Article |
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In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1008855</identifier><identifier>PMID: 32986788</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antiviral activity ; Antiviral Agents - pharmacology ; Biology and Life Sciences ; Care and treatment ; Cell cycle ; Cellular proteins ; Cyclin-dependent kinase 2 ; Cyclin-dependent kinases ; Cyclin-Dependent Kinases - metabolism ; Cytomegalovirus ; Cytomegalovirus - genetics ; Cytomegalovirus - pathogenicity ; Cytomegalovirus infections ; Cytomegalovirus Infections - virology ; Cytoplasm ; Cytoplasm - metabolism ; Cytoplasm - virology ; Deactivation ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA viruses ; Fibroblasts ; Funding ; Gene expression ; Genetic aspects ; Health aspects ; Herpesviridae Infections - metabolism ; Hospitals ; Humans ; Hydrolase ; Immune system ; Inactivation ; Infections ; Infectious diseases ; Investigations ; Kinases ; Laboratories ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Monomeric GTP-Binding Proteins - metabolism ; Mutation ; Pediatrics ; Phosphorylation ; Proteins ; Public health ; Research and Analysis Methods ; Ribonucleotide reductase ; SAM Domain and HD Domain-Containing Protein 1 - genetics ; Viral infections ; Virus Replication - drug effects ; Viruses</subject><ispartof>PLoS pathogens, 2020-09, Vol.16 (9), p.e1008855-e1008855</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 De Meo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 De Meo et al 2020 De Meo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c815t-7b1dce5788aede47421d71b645bf7114421b7d828273372f4b0d13613cc3bda43</citedby><cites>FETCH-LOGICAL-c815t-7b1dce5788aede47421d71b645bf7114421b7d828273372f4b0d13613cc3bda43</cites><orcidid>0000-0001-6146-9302 ; 0000-0003-2904-6371 ; 0000-0001-7605-1531 ; 0000-0002-0869-2596 ; 0000-0001-7675-0762 ; 0000-0002-5114-6953 ; 0000-0002-9226-3734 ; 0000-0003-0432-710X ; 0000-0001-7542-8077 ; 0000-0003-0906-1566 ; 0000-0002-3868-3666 ; 0000-0002-0371-9534</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544099/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544099/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32986788$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:144872056$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Mocarski, Edward</contributor><creatorcontrib>De Meo, Simone</creatorcontrib><creatorcontrib>Dell'Oste, Valentina</creatorcontrib><creatorcontrib>Molfetta, Rosa</creatorcontrib><creatorcontrib>Tassinari, Valentina</creatorcontrib><creatorcontrib>Lotti, Lavinia Vittoria</creatorcontrib><creatorcontrib>Vespa, Simone</creatorcontrib><creatorcontrib>Pignoloni, Benedetta</creatorcontrib><creatorcontrib>Covino, Daniela Angela</creatorcontrib><creatorcontrib>Fantuzzi, Laura</creatorcontrib><creatorcontrib>Bona, Roberta</creatorcontrib><creatorcontrib>Zingoni, Alessandra</creatorcontrib><creatorcontrib>Nardone, Ilaria</creatorcontrib><creatorcontrib>Biolatti, Matteo</creatorcontrib><creatorcontrib>Coscia, Alessandra</creatorcontrib><creatorcontrib>Paolini, Rossella</creatorcontrib><creatorcontrib>Benkirane, Monsef</creatorcontrib><creatorcontrib>Edfors, Fredrik</creatorcontrib><creatorcontrib>Sandalova, Tatyana</creatorcontrib><creatorcontrib>Achour, Adnane</creatorcontrib><creatorcontrib>Hiscott, John</creatorcontrib><creatorcontrib>Landolfo, Santo</creatorcontrib><creatorcontrib>Santoni, Angela</creatorcontrib><creatorcontrib>Cerboni, Cristina</creatorcontrib><title>SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.</description><subject>Antiviral activity</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biology and Life Sciences</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cellular proteins</subject><subject>Cyclin-dependent kinase 2</subject><subject>Cyclin-dependent kinases</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Cytomegalovirus</subject><subject>Cytomegalovirus - genetics</subject><subject>Cytomegalovirus - pathogenicity</subject><subject>Cytomegalovirus infections</subject><subject>Cytomegalovirus Infections - virology</subject><subject>Cytoplasm</subject><subject>Cytoplasm - metabolism</subject><subject>Cytoplasm - virology</subject><subject>Deactivation</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA viruses</subject><subject>Fibroblasts</subject><subject>Funding</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Herpesviridae Infections - metabolism</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hydrolase</subject><subject>Immune system</subject><subject>Inactivation</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Investigations</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Monomeric GTP-Binding Proteins - metabolism</subject><subject>Mutation</subject><subject>Pediatrics</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Public health</subject><subject>Research and Analysis 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phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity</title><author>De Meo, Simone ; Dell'Oste, Valentina ; Molfetta, Rosa ; Tassinari, Valentina ; Lotti, Lavinia Vittoria ; Vespa, Simone ; Pignoloni, Benedetta ; Covino, Daniela Angela ; Fantuzzi, Laura ; Bona, Roberta ; Zingoni, Alessandra ; Nardone, Ilaria ; Biolatti, Matteo ; Coscia, Alessandra ; Paolini, Rossella ; Benkirane, Monsef ; Edfors, Fredrik ; Sandalova, Tatyana ; Achour, Adnane ; Hiscott, John ; Landolfo, Santo ; Santoni, Angela ; Cerboni, Cristina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c815t-7b1dce5788aede47421d71b645bf7114421b7d828273372f4b0d13613cc3bda43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antiviral activity</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biology and Life Sciences</topic><topic>Care and 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Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Meo, Simone</au><au>Dell'Oste, Valentina</au><au>Molfetta, Rosa</au><au>Tassinari, Valentina</au><au>Lotti, Lavinia Vittoria</au><au>Vespa, Simone</au><au>Pignoloni, Benedetta</au><au>Covino, Daniela Angela</au><au>Fantuzzi, Laura</au><au>Bona, Roberta</au><au>Zingoni, Alessandra</au><au>Nardone, Ilaria</au><au>Biolatti, Matteo</au><au>Coscia, Alessandra</au><au>Paolini, Rossella</au><au>Benkirane, Monsef</au><au>Edfors, Fredrik</au><au>Sandalova, Tatyana</au><au>Achour, Adnane</au><au>Hiscott, John</au><au>Landolfo, Santo</au><au>Santoni, Angela</au><au>Cerboni, Cristina</au><au>Mocarski, Edward</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2020-09-28</date><risdate>2020</risdate><volume>16</volume><issue>9</issue><spage>e1008855</spage><epage>e1008855</epage><pages>e1008855-e1008855</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32986788</pmid><doi>10.1371/journal.ppat.1008855</doi><orcidid>https://orcid.org/0000-0001-6146-9302</orcidid><orcidid>https://orcid.org/0000-0003-2904-6371</orcidid><orcidid>https://orcid.org/0000-0001-7605-1531</orcidid><orcidid>https://orcid.org/0000-0002-0869-2596</orcidid><orcidid>https://orcid.org/0000-0001-7675-0762</orcidid><orcidid>https://orcid.org/0000-0002-5114-6953</orcidid><orcidid>https://orcid.org/0000-0002-9226-3734</orcidid><orcidid>https://orcid.org/0000-0003-0432-710X</orcidid><orcidid>https://orcid.org/0000-0001-7542-8077</orcidid><orcidid>https://orcid.org/0000-0003-0906-1566</orcidid><orcidid>https://orcid.org/0000-0002-3868-3666</orcidid><orcidid>https://orcid.org/0000-0002-0371-9534</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7374 |
| ispartof | PLoS pathogens, 2020-09, Vol.16 (9), p.e1008855-e1008855 |
| issn | 1553-7374 1553-7366 1553-7374 |
| language | eng |
| recordid | cdi_plos_journals_2451547451 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PLoS_OA刊; EZB-FREE-00999 freely available EZB journals; PubMed Central; SWEPUB Freely available online; PubMed Central Open Access |
| subjects | Antiviral activity Antiviral Agents - pharmacology Biology and Life Sciences Care and treatment Cell cycle Cellular proteins Cyclin-dependent kinase 2 Cyclin-dependent kinases Cyclin-Dependent Kinases - metabolism Cytomegalovirus Cytomegalovirus - genetics Cytomegalovirus - pathogenicity Cytomegalovirus infections Cytomegalovirus Infections - virology Cytoplasm Cytoplasm - metabolism Cytoplasm - virology Deactivation Deoxyribonucleic acid Development and progression DNA DNA viruses Fibroblasts Funding Gene expression Genetic aspects Health aspects Herpesviridae Infections - metabolism Hospitals Humans Hydrolase Immune system Inactivation Infections Infectious diseases Investigations Kinases Laboratories Medicin och hälsovetenskap Medicine Medicine and Health Sciences Monomeric GTP-Binding Proteins - metabolism Mutation Pediatrics Phosphorylation Proteins Public health Research and Analysis Methods Ribonucleotide reductase SAM Domain and HD Domain-Containing Protein 1 - genetics Viral infections Virus Replication - drug effects Viruses |
| title | SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity |
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