Toward system-level understanding of baculovirus–host cell interactions: from molecular fundamental studies to large-scale proteomics approaches

Monteiro, Francisca; Carinhas, Nuno; Carrondo, Manuel J.T.; Bernal, Vicente; Alves, Paula M.

doi:10.3389/fmicb.2012.00391

Cited by 47 publications

(52 citation statements)

References 181 publications

(203 reference statements)

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“…Because of the link between the DDR and IAP destruction, the identity of the kinase(s) responsible is of significant interest. MAPK kinases orchestrate many cell signaling pathways, including those regulating innate immunity, apoptosis, stress, and the DDR (reviewed by references 47,[48][49][50]. In vertebrates, the DDR can activate MAPK, including p38 (48,49).…”

Section: Figmentioning

confidence: 99%

Insect Inhibitor-of-Apoptosis (IAP) Proteins Are Negatively Regulated by Signal-Induced N-Terminal Degrons Absent within Viral IAP Proteins

Vandergaast

Mitchell

Byers

et al. 2015

J Virol

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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 Nterminal 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 signalresponsive 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. IMPORTANCEApoptosis 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 ...

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Section: Figmentioning

confidence: 99%

Insect Inhibitor-of-Apoptosis (IAP) Proteins Are Negatively Regulated by Signal-Induced N-Terminal Degrons Absent within Viral IAP Proteins

Vandergaast

Mitchell

Byers

et al. 2015

J Virol

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“…Stimulation of a heat shock response during baculovirus infection and its importance for virus amplification has been frequently mentioned in the literature [23][24][25][26]. However, the viral factors that are responsible for this effect and the mechanism underlying the interaction between viral factors and HSPs are still unclear [27]. Here, we show that by inhibiting the heat shock response, IE2 protein became degraded and could not accumulate.…”

Section: Introductionmentioning

confidence: 60%

Baculovirus IE2 stimulates the expression of heat shock proteins in insect and mammalian cells to facilitate its proper functioning

Chao¹

2016

2016 International Congress of Entomology

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Baculoviruses have gained popularity as pest control agents and for protein production in insect systems. These viruses are also becoming popular for gene expression, tissue engineering and gene therapy in mammalian systems. Baculovirus infection triggers a heat shock response, and this response is crucial for its successful infection of host insect cells. However, the viral protein(s) or factor(s) that trigger this response are not yet clear. Previously, we revealed that IE2-an early gene product of the baculovirus-could form unique nuclear bodies for the strong trans-activation of various promoters in mammalian cells. Here, we purified IE2 nuclear bodies from Vero E6 cells and investigated the associated proteins by using mass spectrometry. Heat shock proteins (HSPs) were found to be one of the major IE2-associated proteins. Our experiments show that HSPs are greatly induced by IE2 and are crucial for the trans-activation function of IE2. Interestingly, blocking both heat shock protein expression and the proteasome pathway preserved the IE2 protein and its nuclear body structure, and revived its function. These observations reveal that HSPs do not function directly to assist the formation of the nuclear body structure, but may rather protect IE2 from proteasome degradation. Aside from functional studies in mammalian cells, we also show that HSPs were stimulated and required to determine IE2 protein levels, in insect cells infected with baculovirus. Upon inhibiting the expression of heat shock proteins, baculovirus IE2 was substantially suppressed, resulting in a significantly suppressed viral titer. Thus, we demonstrate a unique feature in that IE2 can function in both insect and nonhost mammalian cells to stimulate HSPs, which may be associated with IE2 stabilization and lead to the protection of the its strong gene activation function in mammalian cells. On the other hand, during viral infection in insect cells, IE2 could also strongly stimulate HSPs and ultimately affect viral replication.

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“…No NPV-encoded genes have been linked to energy metabolism (Chen et al, 2001;Nguyen et al, 2013). Similarly, the baculovirus manipulation of the host's metabolic machinery has been proposed to be critical for their successful propagation in hosts (Monteiro et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Digital gene expression analysis of Helicoverpa armigera in the early stage of infection with Helicoverpa armigera nucleopolyhedrovirus

Xiu

et al. 2015

Journal of Invertebrate Pathology

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Toward system-level understanding of baculovirus–host cell interactions: from molecular fundamental studies to large-scale proteomics approaches

Cited by 47 publications

References 181 publications

Insect Inhibitor-of-Apoptosis (IAP) Proteins Are Negatively Regulated by Signal-Induced N-Terminal Degrons Absent within Viral IAP Proteins

Insect Inhibitor-of-Apoptosis (IAP) Proteins Are Negatively Regulated by Signal-Induced N-Terminal Degrons Absent within Viral IAP Proteins

Baculovirus IE2 stimulates the expression of heat shock proteins in insect and mammalian cells to facilitate its proper functioning

Digital gene expression analysis of Helicoverpa armigera in the early stage of infection with Helicoverpa armigera nucleopolyhedrovirus

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