Abstract:
UNLABELLED:Inhibitor-of-apoptosis (IAP) proteins are key regulators of the innate antiviral response by virtue of their capacity to respond to signals affecting cell survival. In insects, wherein the host IAP provides a primary restriction to apoptosis, diverse viruses trigger rapid IAP depletion that initiates caspase-mediated apoptosis, thereby limiting virus multiplication. We report here that the N-terminal leader of two insect IAPs, Spodoptera frugiperda SfIAP and Drosophila melanogaster DIAP1, contain distinct instability motifs that regulate IAP turnover and apoptotic consequences. Functioning as a protein degron, the cellular IAP leader dramatically shortened the life span of a long-lived viral IAP (Op-IAP3) when fused to its N terminus. The SfIAP degron contains mitogen-activated kinase (MAPK)-like regulatory sites, responsible for MAPK inhibitor-sensitive phosphorylation of SfIAP. Hyperphosphorylation correlated with increased SfIAP turnover independent of the E3 ubiquitin-ligase activity of the SfIAP RING, which also regulated IAP stability. Together, our findings suggest that the SfIAP phospho-degron responds rapidly to a signal-activated kinase cascade, which regulates SfIAP levels and thus apoptosis. The N-terminal leader of dipteran DIAP1 also conferred virus-induced IAP depletion by a caspase-independent mechanism. DIAP1 instability mapped to previously unrecognized motifs that are not found in lepidopteran IAPs. Thus, the leaders of cellular IAPs from diverse insects carry unique signal-responsive degrons that control IAP turnover. Rapid response pathways that trigger IAP degradation and initiate apoptosis independent of canonical prodeath gene (Reaper-Grim-Hid) expression may provide important innate immune advantages. Furthermore, the elimination of these response motifs within viral IAPs, including those of baculoviruses, explains their unusual stability and their potent antiapoptotic activity. IMPORTANCE:Apoptosis is an effective means by which a host controls virus infection. In insects, inhibitor-of-apoptosis (IAP) proteins act as regulatory sentinels by responding to cellular signals that determine the fate of infected cells. We discovered that lepidopteran (moth and butterfly) IAPs, which are degraded upon baculovirus infection, are controlled by a conserved phosphorylation-sensitive degron within the IAP N-terminal leader. The degron likely responds to virus-induced kinase-specific signals for degradation through SKP1/Cullin/F-box complex-mediated ubiquitination. Such signal-induced destruction of cellular IAPs is distinct from degradation caused by well-known IAP antagonists, which act to expel IAP-bound caspases. The major implication of this study is that insects have multiple signal-responsive mechanisms by which the sentinel IAPs are actively degraded to initiate host apoptosis. Such diversity of pathways likely provides insects with rapid and efficient strategies for pathogen control. Furthermore, the absence of analogous degrons in virus-encoded IAPs explains their relative stability and antiapoptotic potency.
journal_name
J Viroljournal_title
Journal of virologyauthors
Vandergaast R,Mitchell JK,Byers NM,Friesen PDdoi
10.1128/JVI.03659-14subject
Has Abstractpub_date
2015-04-01 00:00:00pages
4481-93issue
8eissn
0022-538Xissn
1098-5514pii
JVI.03659-14journal_volume
89pub_type
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pub_type: 杂志文章
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pub_type: 杂志文章
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doi:10.1128/JVI.73.7.5520-5526.1999
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doi:10.1128/JVI.01178-06
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pub_type: 杂志文章
doi:10.1128/JVI.69.9.5754-5762.1995
更新日期:1995-09-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.7.4133-4141.1993
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.8.4103-4107.2002
更新日期:2002-04-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00103-16
更新日期:2016-04-14 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.20.13082-13093.2005
更新日期:2005-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.30.2.637-641.1979
更新日期:1979-05-01 00:00:00
abstract::Secondary cultures of chicken embryo fibroblasts were infected with the Schmidt Ruppin strain of Rous sarcoma virus (RSV). Five days after infection, the medium was replaced at 2-h intervals with phosphate-free Eagle medium containing 50 muCi of [32P]orthophosphate per ml. Virus was collected by centrifugation, and th...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.15.1.161-166.1975
更新日期:1975-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.30.2.462-471.1979
更新日期:1979-05-01 00:00:00
abstract::Human respiratory syncytial virus (RSV) is a serious respiratory pathogen in infants and young children as well as elderly and immunocompromised populations. However, no RSV vaccines are available. We have explored the potential of virus-like particles (VLPs) as an RSV vaccine candidate. VLPs composed entirely of RSV ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01861-10
更新日期:2011-01-01 00:00:00
abstract::The swine-specific coronavirus transmissible gastroenteritis virus (TGEV) uses pig aminopeptidase-N (pAPN) as a cellular receptor. We showed that the human aminopeptidase-N (hAPN) cannot substitute for pAPN in this respect, although the two enzymes have 80% amino acid sequence identity. In order to map the TGEV bindin...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.8.5216-5224.1994
更新日期:1994-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.10.5114-5122.1990
更新日期:1990-10-01 00:00:00