Viral IAPs, then and now

Clem, Rollie J.

doi:10.1016/j.semcdb.2015.01.011

Cited by 54 publications

(55 citation statements)

References 76 publications

(101 reference statements)

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“…response components. For example, the characterization of the viral inhibitor of apoptosis protein (vIAP) in Baculoviridae and later Entomopoxvirinae led to the identification of the host cIAPs, which regulate caspase activity in insects and in vertebrates (22,40). Similarly, the identification of a viral cytokine in the genome of Herpesvirus saimiri paved the way for the discovery of the mammalian cytokine IL-17 and its receptor (41).…”

Section: Resultsmentioning

confidence: 99%

“…These VSAs include suicide substrates for caspases (e.g., AcMNPV-p35, AMP-p33), and inhibitors (vIAPs), which bind to their N terminus (reviewed in ref. 22).…”

Section: Resultsmentioning

confidence: 99%

“…inhibitors of RNAi or apoptosis (known as VSRs or VSAs, for viral suppressors of RNAi or apotosis, respectively), attesting to the restrictive pressures exerted by these host antiviral mechanisms in insects (20)(21)(22)(23)(24)(25)(26).…”

Section: Significancementioning

confidence: 99%

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Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila

Lamiable

Kellenberger

Kemp

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.

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Section: Resultsmentioning

confidence: 99%

“…These VSAs include suicide substrates for caspases (e.g., AcMNPV-p35, AMP-p33), and inhibitors (vIAPs), which bind to their N terminus (reviewed in ref. 22).…”

Section: Resultsmentioning

confidence: 99%

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Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila

Lamiable

Kellenberger

Kemp

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…3B; see also reference 27). Second, Op-IAP3 is stable compared to cellular IAPs despite the presence of a RING-encoded E3 ubiquitin ligase (5). This property suggests that Op-IAP3 is resistant to RINGmediated autoubiquitination, a process that contributes to cellular IAP instability (32).…”

Section: Discussionmentioning

confidence: 99%

“…This highly conserved self-destruct process is regulated by the inhibitor of apoptosis (IAP) proteins, a family of critical survival factors that are also involved in development, mitosis, inflammation, and cancer (reviewed in references 1, 2, 3, and 4). Multiple insect DNA viruses, including the baculoviruses, entomopoxviruses, iridoviruses, nudiviruses, and asfarviruses, encode IAPs to inhibit virus replication-induced apoptosis and thereby expedite virus multiplication and dissemination (5,6). Of these viruses, IAPs from the baculoviruses are the best characterized.…”

Section: Importancementioning

confidence: 99%

Baculovirus Inhibitor-of-Apoptosis Op-IAP3 Blocks Apoptosis by Interaction with and Stabilization of a Host Insect Cellular IAP

Byers

Vandergaast

Friesen

2016

J Virol

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Baculovirus-encoded inhibitor of apoptosis (IAP) proteins likely evolved from their host cell IAP homologs, which function as critical regulators of cell death. Despite their striking relatedness to cellular IAPs, including the conservation of two baculovirus IAP repeat (BIR) domains and a C-terminal RING, viral IAPs use an unresolved mechanism to suppress apoptosis in insects. To define this mechanism, we investigated Op-IAP3, the prototypical IAP from baculovirus OpMNPV. We found that Op-IAP3 forms a stable complex with SfIAP, the native, short-lived IAP of host insect Spodoptera frugiperda. Long-lived Op-IAP3 prevented virus-induced SfIAP degradation, which normally causes caspase activation and apoptosis. In uninfected cells, Op-IAP3 also increased SfIAP steady-state levels and extended SfIAP's half-life. Conversely, SfIAP stabilization was lost or reversed in the presence of mutated Op-IAP3 that was engineered for reduced stability. Thus, Op-IAP3 stabilizes SfIAP and preserves its antiapoptotic function. In contrast to SfIAP, Op-IAP3 failed to bind or inhibit native Spodoptera caspases. Furthermore, BIR mutations that abrogate binding of well-conserved IAP antagonists did not affect Op-IAP3's capacity to prevent virus-induced apoptosis. Remarkably, Op-IAP3 also failed to prevent apoptosis when endogenous SfIAP was ablated by RNA silencing. Thus, Op-IAP3 requires SfIAP as a cofactor. Our findings suggest a new model wherein Op-IAP3 interacts directly with SfIAP to maintain its intracellular level, thereby suppressing virus-induced apoptosis indirectly. Consistent with this model, Op-IAP3 has evolved an intrinsic stability that may serve to repress signal-induced turnover and autoubiquitination when bound to its targeted cellular IAP. IMPORTANCEThe IAPs were first discovered in baculoviruses because of their potency for preventing apoptosis. However, the antiapoptotic mechanism of viral IAPs in host insects has been elusive. We show here that the prototypical viral IAP, Op-IAP3, blocks apoptosis indirectly by associating with unstable, autoubiquitinating host IAP in such a way that cellular IAP levels and antiapoptotic activities are maintained. This mechanism explains Op-IAP3's requirement for native cellular IAP as a cofactor and the dispensability of caspase inhibition. Viral IAP-mediated preservation of the host IAP homolog capitalizes on normal IAP-IAP interactions and is likely the result of viral IAP evolution in which degron-mediated destabilization and ubiquitination potential have been reduced. This mechanism illustrates another novel means by which DNA viruses incorporate host death regulators that are modified for resistance to host regulatory controls for the purpose of suppressing host cell apoptosis and acquiring replication advantages.A poptosis is an important defense against virus infection. This highly conserved self-destruct process is regulated by the inhibitor of apoptosis (IAP) proteins, a family of critical survival factors that are also involved in development, mitosis, inflam...

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The Ecosystem Role of Viruses Affecting Eukaryotes

Hurst

2022

Assessing the Microbiological Health of Ecosystems

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Viral IAPs, then and now

Cited by 54 publications

References 76 publications

Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila

Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila

Baculovirus Inhibitor-of-Apoptosis Op-IAP3 Blocks Apoptosis by Interaction with and Stabilization of a Host Insect Cellular IAP

The Ecosystem Role of Viruses Affecting Eukaryotes

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