2.50
Hdl Handle:
http://hdl.handle.net/10033/621100
Title:
UL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene.
Authors:
Chaudhry, M Zeeshan; Kasmapour, Bahram; Plaza-Sirvent, Carlos; Bajagic, Milica; Casalegno Garduño, Rosaely; Borkner, Lisa; Lenac Roviš, Tihana; Scrima, Andrea; Jonjic, Stipan; Schmitz, Ingo ( 0000-0002-5360-0419 ) ; Cicin-Sain, Luka ( 0000-0003-3978-778X )
Abstract:
Apoptosis is an important defense mechanism mounted by the immune system to control virus replication. Hence, cytomegaloviruses (CMV) evolved and acquired numerous anti-apoptotic genes. The product of the human CMV (HCMV) UL36 gene, pUL36 (also known as vICA), binds to pro-caspase-8, thus inhibiting death-receptor apoptosis and enabling viral replication in differentiated THP-1 cells. In vivo studies of the function of HCMV genes are severely limited due to the strict host specificity of cytomegaloviruses, but CMV orthologues that co-evolved with other species allow the experimental study of CMV biology in vivo. The mouse CMV (MCMV) homolog of the UL36 gene is called M36, and its protein product (pM36) is a functional homolog of vICA that binds to murine caspase-8 and inhibits its activation. M36-deficient MCMV is severely growth impaired in macrophages and in vivo. Here we show that pUL36 binds to the murine pro-caspase-8, and that UL36 expression inhibits death-receptor apoptosis in murine cells and can replace M36 to allow MCMV growth in vitro and in vivo. We generated a chimeric MCMV expressing the UL36 ORF sequence instead of the M36 one. The newly generated MCMV(UL36) inhibited apoptosis in macrophage lines RAW 264.7, J774A.1, and IC-21 and its growth was rescued to wild type levels. Similarly, growth was rescued in vivo in the liver and spleen, but only partially in the salivary glands of BALB/c and C57BL/6 mice. In conclusion, we determined that an immune-evasive HCMV gene is conserved enough to functionally replace its MCMV counterpart and thus allow its study in an in vivo setting. As UL36 and M36 proteins engage the same molecular host target, our newly developed model can facilitate studies of anti-viral compounds targeting pUL36 in vivo.
Affiliation:
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
UL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene. 2017, 7:312 Front Cell Infect Microbiol
Journal:
Frontiers in cellular and infection microbiology
Issue Date:
2017
URI:
http://hdl.handle.net/10033/621100
DOI:
10.3389/fcimb.2017.00312
PubMed ID:
28770171
Type:
Article
Language:
en
ISSN:
2235-2988
Appears in Collections:
publications of the AG system-oriented immunologyand infection research (SIME); publications of the research group immune aging and chronic infections (IMCI); research group of structural biology of autophagy (SBAU)

Full metadata record

DC FieldValue Language
dc.contributor.authorChaudhry, M Zeeshanen
dc.contributor.authorKasmapour, Bahramen
dc.contributor.authorPlaza-Sirvent, Carlosen
dc.contributor.authorBajagic, Milicaen
dc.contributor.authorCasalegno Garduño, Rosaelyen
dc.contributor.authorBorkner, Lisaen
dc.contributor.authorLenac Roviš, Tihanaen
dc.contributor.authorScrima, Andreaen
dc.contributor.authorJonjic, Stipanen
dc.contributor.authorSchmitz, Ingoen
dc.contributor.authorCicin-Sain, Lukaen
dc.date.accessioned2017-09-11T10:30:46Z-
dc.date.available2017-09-11T10:30:46Z-
dc.date.issued2017-
dc.identifier.citationUL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene. 2017, 7:312 Front Cell Infect Microbiolen
dc.identifier.issn2235-2988-
dc.identifier.pmid28770171-
dc.identifier.doi10.3389/fcimb.2017.00312-
dc.identifier.urihttp://hdl.handle.net/10033/621100-
dc.description.abstractApoptosis is an important defense mechanism mounted by the immune system to control virus replication. Hence, cytomegaloviruses (CMV) evolved and acquired numerous anti-apoptotic genes. The product of the human CMV (HCMV) UL36 gene, pUL36 (also known as vICA), binds to pro-caspase-8, thus inhibiting death-receptor apoptosis and enabling viral replication in differentiated THP-1 cells. In vivo studies of the function of HCMV genes are severely limited due to the strict host specificity of cytomegaloviruses, but CMV orthologues that co-evolved with other species allow the experimental study of CMV biology in vivo. The mouse CMV (MCMV) homolog of the UL36 gene is called M36, and its protein product (pM36) is a functional homolog of vICA that binds to murine caspase-8 and inhibits its activation. M36-deficient MCMV is severely growth impaired in macrophages and in vivo. Here we show that pUL36 binds to the murine pro-caspase-8, and that UL36 expression inhibits death-receptor apoptosis in murine cells and can replace M36 to allow MCMV growth in vitro and in vivo. We generated a chimeric MCMV expressing the UL36 ORF sequence instead of the M36 one. The newly generated MCMV(UL36) inhibited apoptosis in macrophage lines RAW 264.7, J774A.1, and IC-21 and its growth was rescued to wild type levels. Similarly, growth was rescued in vivo in the liver and spleen, but only partially in the salivary glands of BALB/c and C57BL/6 mice. In conclusion, we determined that an immune-evasive HCMV gene is conserved enough to functionally replace its MCMV counterpart and thus allow its study in an in vivo setting. As UL36 and M36 proteins engage the same molecular host target, our newly developed model can facilitate studies of anti-viral compounds targeting pUL36 in vivo.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleUL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalFrontiers in cellular and infection microbiologyen

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