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Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor
Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate, and adaptive viral immune evasion. Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2020-08, Vol.117 (31), p.18771-18779 |
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| container_end_page | 18779 |
| container_issue | 31 |
| container_start_page | 18771 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 117 |
| creator | Fletcher-Etherington, Alice Nobre, Luis Nightingale, Katie Antrobus, Robin Nichols, Jenna Davison, Andrew J. Stanton, Richard J. Weekes, Michael P. |
| description | Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate, and adaptive viral immune evasion. Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key terminal mediator of cellular necroptosis, was rapidly and persistently degraded by the minimally passaged HCMV strain Merlin but not the extensively passaged strain AD169. The strain Merlin viral inhibitor of apoptosis pUL36 was necessary and sufficient both to degrade MLKL and to inhibit necroptosis. Furthermore, mutation of pUL36 Cys131 abrogated MLKL degradation and restored necroptosis. As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of procaspase-8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death. |
| doi_str_mv | 10.1073/pnas.2001887117 |
| format | article |
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Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key terminal mediator of cellular necroptosis, was rapidly and persistently degraded by the minimally passaged HCMV strain Merlin but not the extensively passaged strain AD169. The strain Merlin viral inhibitor of apoptosis pUL36 was necessary and sufficient both to degrade MLKL and to inhibit necroptosis. Furthermore, mutation of pUL36 Cys131 abrogated MLKL degradation and restored necroptosis. As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of procaspase-8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2001887117</identifier><identifier>PMID: 32690704</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Apoptosis ; Apoptosis - physiology ; Biological Sciences ; Cell death ; Cells, Cultured ; Cytomegalovirus ; Cytomegalovirus - chemistry ; Cytomegalovirus - metabolism ; Cytomegalovirus - pathogenicity ; Cytomegalovirus Infections - metabolism ; Cytomegalovirus Infections - virology ; Degradation ; Humans ; Kinases ; MAP kinase ; Mutation ; Necroptosis ; Necroptosis - physiology ; Protein Binding ; Proteins ; Proteolysis ; Proteomics ; Viral Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-08, Vol.117 (31), p.18771-18779</ispartof><rights>Copyright © 2020 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Aug 4, 2020</rights><rights>Copyright © 2020 the Author(s). 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As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of procaspase-8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.</description><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Biological Sciences</subject><subject>Cell death</subject><subject>Cells, Cultured</subject><subject>Cytomegalovirus</subject><subject>Cytomegalovirus - chemistry</subject><subject>Cytomegalovirus - metabolism</subject><subject>Cytomegalovirus - pathogenicity</subject><subject>Cytomegalovirus Infections - metabolism</subject><subject>Cytomegalovirus Infections - virology</subject><subject>Degradation</subject><subject>Humans</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>Mutation</subject><subject>Necroptosis</subject><subject>Necroptosis - physiology</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Proteomics</subject><subject>Viral Proteins - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpdkEtLAzEUhYMotj7WrpRCN25Gb16TZCNIUSsU3Og6pGmmTpmZjMmM0H9vSmt9rO7ifOdwz0HoAsMNBkFv28bEGwKApRQYiwM0xKBwljMFh2gIQEQmGWEDdBLjCgAUl3CMBpTkCgSwIRpP-9o0I7vufO2WpvKfZejjqA2-c2Uzat9mND9DR4Wpojvf3VP0-vjwOplms5en58n9LLOM0S6zspDKWpdT5rAsbIGdJHyBuTUSC3CgyLzIhaTAqQOwXDHOjXDJvVBzSU_R3Ta27ee1W1jXdMFUug1lbcJae1Pqv0pTvuul_9SCYYYlTQHXu4DgP3oXO12X0bqqMo3zfdSEES4Vo4QkdPwPXfk-NKldoigDQXKsEnW7pWzwMQZX7J_BoDf7683--mf_5Lj63WHPfw-egMstsIqdD3s9yZTnFOgXPBmJqQ</recordid><startdate>20200804</startdate><enddate>20200804</enddate><creator>Fletcher-Etherington, Alice</creator><creator>Nobre, Luis</creator><creator>Nightingale, Katie</creator><creator>Antrobus, Robin</creator><creator>Nichols, Jenna</creator><creator>Davison, Andrew J.</creator><creator>Stanton, Richard J.</creator><creator>Weekes, Michael P.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3196-5545</orcidid><orcidid>https://orcid.org/0000-0003-0093-7170</orcidid><orcidid>https://orcid.org/0000-0002-6799-1182</orcidid><orcidid>https://orcid.org/0000-0002-4991-9128</orcidid><orcidid>https://orcid.org/0000-0001-9958-4699</orcidid><orcidid>https://orcid.org/0000-0001-7313-9247</orcidid><orcidid>https://orcid.org/0000-0003-0467-8989</orcidid></search><sort><creationdate>20200804</creationdate><title>Human cytomegalovirus protein pUL36</title><author>Fletcher-Etherington, Alice ; 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| subjects | Apoptosis Apoptosis - physiology Biological Sciences Cell death Cells, Cultured Cytomegalovirus Cytomegalovirus - chemistry Cytomegalovirus - metabolism Cytomegalovirus - pathogenicity Cytomegalovirus Infections - metabolism Cytomegalovirus Infections - virology Degradation Humans Kinases MAP kinase Mutation Necroptosis Necroptosis - physiology Protein Binding Proteins Proteolysis Proteomics Viral Proteins - metabolism |
| title | Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor |
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