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

2015 ◽  
Vol 90 (1) ◽  
pp. 533-544 ◽  
Author(s):  
Nathaniel M. Byers ◽  
Rianna L. Vandergaast ◽  
Paul D. Friesen
Keyword(s):  
Host Cell ◽  
Stable Complex ◽  
Inhibitor Of Apoptosis ◽  
Dna Viruses ◽  
Content Type ◽  
Host Insect ◽  
Host Cell Apoptosis ◽  
Steady State Levels ◽  
Induced Apoptosis ◽  
Regulatory Controls

ABSTRACTBaculovirus-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 insectSpodoptera 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 nativeSpodopteracaspases. 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.

scholarly journals Host Insect Inhibitor-of-Apoptosis SfIAP Functionally Replaces Baculovirus IAP but Is Differentially Regulated by Its N-Terminal Leader

2010 ◽  
Vol 84 (21) ◽  
pp. 11448-11460 ◽  
Author(s):  
Rebecca J. Cerio ◽  
Rianna Vandergaast ◽  
Paul D. Friesen
Keyword(s):  
Selective Advantage ◽  
Biochemical Properties ◽  
Inhibitor Of Apoptosis ◽  
Loss Of Function ◽  
Wild Type ◽  
Host Insect ◽  
Orgyia Pseudotsugata ◽  
Induced Apoptosis ◽  
Lepidopteran Host ◽  
Maximal Stability

ABSTRACT The inhibitor-of-apoptosis (IAP) proteins encoded by baculoviruses bear a striking resemblance to the cellular IAP homologs of their invertebrate hosts. By virtue of the acquired selective advantage of blocking virus-induced apoptosis, baculoviruses may have captured cellular IAP genes that subsequently evolved for virus-specific objectives. To compare viral and host IAPs, we defined antiapoptotic properties of SfIAP, the principal cellular IAP of the lepidopteran host Spodoptera frugiperda. We report here that SfIAP prevented virus-induced apoptosis as well as viral Op-IAP3 (which is encoded by the Orgyia pseudotsugata nucleopolyhedrovirus) when overexpressed from the baculovirus genome. Like Op-IAP3, SfIAP blocked apoptosis at a step prior to caspase activation. Both of the baculovirus IAP repeats (BIRs) were required for SfIAP function. Moreover, deletion of the C-terminal RING motif generated a loss-of-function SfIAP that interacted and dominantly interfered with wild-type SfIAP. Like Op-IAP3, wild-type SfIAP formed intracellular homodimers, suggesting that oligomerization is a functional requirement for both cellular and viral IAPs. SfIAP possesses a ∼100-residue N-terminal leader domain, which is absent among all viral IAPs. Remarkably, deletion of the leader yielded a fully functional SfIAP with dramatically increased protein stability. Thus, the SfIAP leader contains an instability motif that may confer regulatory options for cellular IAPs that baculovirus IAPs have evolved to bypass for maximal stability and antiapoptotic potency. Our findings that SfIAP and viral IAPs have common motifs, share multiple biochemical properties including oligomerization, and act at the same step to block apoptosis support the hypothesis that baculoviral IAPs were derived by acquisition of host insect IAPs.

scholarly journals Porcine Parvovirus Infection Causes Pig Placenta Tissue Damage Involving Nonstructural Protein 1 (NS1)-Induced Intrinsic ROS/Mitochondria-Mediated Apoptosis

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 389 ◽  
Author(s):  
Zhang ◽  
Fan ◽  
Li ◽  
Liang ◽  
Huo ◽  
...  
Keyword(s):  
Host Cell ◽  
Cell Apoptosis ◽  
Nonstructural Protein ◽  
Placental Tissue ◽  
Reproductive Failure ◽  
Porcine Parvovirus ◽  
Nonstructural Protein 1 ◽  
Host Cell Apoptosis ◽  
Tissue Damages ◽  
Induced Apoptosis

Porcine parvovirus (PPV) is an important pathogen causing reproductive failure in pigs. PPV-induced cell apoptosis has been recently identified as being involved in PPV-induced placental tissue damages resulting in reproductive failure. However, the molecular mechanism was not fully elucidated. Here we demonstrate that PPV nonstructural protein 1 (NS1) can induce host cell apoptosis and death, thereby indicating the NS1 may play a crucial role in PPV-induced placental tissue damages and reproductive failure. We have found that NS1-induced apoptosis was significantly inhibited by caspase 9 inhibitor, but not caspase 8 inhibitor, and transfection of NS1 gene into PK-15 cells significantly inhibited mitochondria-associated antiapoptotic molecules Bcl-2 and Mcl-1 expressions and enhanced proapoptotic molecules Bax, P21, and P53 expressions, suggesting that NS1-induced apoptosis is mainly through the mitochondria-mediated intrinsic apoptosis pathway. We also found that both PPV infection and NS1 vector transfection could cause host DNA damage resulting in cell cycle arrest at the G1 and G2 phases, trigger mitochondrial ROS accumulation resulting in mitochondria damage, and therefore, induce the host cell apoptosis. This study provides a molecular basis for elucidating PPV-induced cell apoptosis and reproductive failure.

scholarly journals The ZIKA Virus Delays Cell Death Through the Anti-Apoptotic Bcl-2 Family Proteins

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1338 ◽  
Author(s):  
Jonathan Turpin ◽  
Etienne Frumence ◽  
Philippe Desprès ◽  
Wildriss Viranaicken ◽  
Pascale Krejbich-Trotot
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Zika Virus ◽  
Congenital Defects ◽  
Host Cell Apoptosis ◽  
Family Protein ◽  
Global Concern ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Replicon Type

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

scholarly journals Conversion of Commensal Escherichia coli K-12 to an Invasive Form via Expression of a Mutant Histone-Like Protein

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Preeti Koli ◽  
Sudhanshu Sudan ◽  
David Fitzgerald ◽  
Sankar Adhya ◽  
Sudeshna Kar
Keyword(s):  
Escherichia Coli ◽  
Host Cell ◽  
Cell Apoptosis ◽  
Transcription Profile ◽  
Intracellular Replication ◽  
Content Type ◽  
E Coli ◽  
Host Cell Apoptosis ◽  
K 12 ◽  
Cellular Transcription

ABSTRACTThe HUαE38K, V42Lmutant of the bacterial histone-like protein HU causes a major change in the transcription profile of the commensal organismEscherichia coliK-12 (Kar S, Edgar R, Adhya S, Proc. Natl. Acad. Sci. U. S. A. 102:16397–16402, 2005). Among the upregulated genes are several related to pathogenic interactions with mammalian cells, as evidenced by the expression of curli fibers, Ivy, and hemolysin E. WhenE. coliK-12/ HUαE38K, V42Lwas added to Int-407 cells, there was host cell invasion, phagosomal disruption, and intracellular replication. The invasive trait was also retained in a murine ileal loop model and intestinal explant assays. In addition to invasion, the internalized bacteria caused a novel subversion of host cell apoptosis through modification and regulation of the BH3-only proteins BimELand Puma. Changes in the transcription profile were attributed to positive supercoiling of DNA leading to the altered availability of relevant promoters. Using theE. coliK-12/HUαE38K, V42Lvariant as a model, we propose that traditional commensalE. colican adopt an invasive lifestyle through reprogramming its cellular transcription, without gross genetic changes.IMPORTANCEEscherichia coliK-12 is well established as a benign laboratory strain and a human intestinal commensal. Recent evidences, however, indicate that the typical noninvasive nature of residentE. colican be reversed under specific circumstances even in the absence of any major genomic flux. We previously engineered anE. colistrain with a mutant histone-like protein, HU, which exhibited significant changes in nucleoid organization and global transcription. Here we showed that the changes induced by the mutant HU have critical functional consequences: from a strict extracellular existence, the mutantE. coliadopts an almost obligate intracellular lifestyle. The internalizedE. coliexhibits many of the prototypical characteristics of traditional intracellular bacteria, like phagosomal escape, intracellular replication, and subversion of host cell apoptosis. We suggest thatE. coliK-12 can switch between widely divergent lifestyles in relation to mammalian host cells by reprogramming its cellular transcription program and without gross changes in its genomic content.

scholarly journals The ZIKA Virus Delays Cell Death through the Anti-Apoptotic Bcl-2 Family Proteins

2019 ◽  
Author(s):  
Jonathan Turpin ◽  
Etienne Frumence ◽  
Philippe Desprès ◽  
Wildriss Viranaïcken ◽  
Pascale Krejbich-Trotot
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Zika Virus ◽  
Congenital Defects ◽  
Host Cell Apoptosis ◽  
Family Protein ◽  
Global Concern ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Replicon Type

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

scholarly journals Antiapoptotic Activity of Coxiella burnetii Effector Protein AnkG Is Controlled by p32-Dependent Trafficking

2014 ◽  
Vol 82 (7) ◽  
pp. 2763-2771 ◽  
Author(s):  
Rita A. Eckart ◽  
Stephanie Bisle ◽  
Jan Schulze-Luehrmann ◽  
Irene Wittmann ◽  
Jonathan Jantsch ◽  
...  
Keyword(s):  
Host Cell ◽  
Nuclear Localization ◽  
Coxiella Burnetii ◽  
Intracellular Localization ◽  
Mitochondrial Protein ◽  
Effector Proteins ◽  
Content Type ◽  
Type Iv ◽  
Antiapoptotic Activity ◽  
Induced Apoptosis

ABSTRACTIntracellular bacterial pathogens frequently inhibit host cell apoptosis to ensure survival of their host, thereby allowing bacterial propagation. The obligate intracellular pathogenCoxiella burnetiidisplays antiapoptotic activity which depends on a functional type IV secretion system (T4SS). Accordingly, antiapoptotic T4SS effector proteins, like AnkG, have been identified. AnkG inhibits pathogen-induced apoptosis, possibly by binding to the host cell mitochondrial protein p32 (gC1qR). However, the molecular mechanism of AnkG activity remains unknown. Here, we demonstrate that ectopically expressed AnkG associates with mitochondria and traffics into the nucleus after apoptosis induction, although AnkG lacks a predicted nuclear localization signal. We identified the p32 interaction region in AnkG and constructed an AnkG mutant (AnkGR22/23S) unable to bind to p32. By using this mutant, we found that intracellular localization and trafficking of AnkG into the nucleus are dependent on binding to p32. Furthermore, we demonstrated that nuclear localization of AnkG but not binding to p32 is required for apoptosis inhibition. Thus, the antiapoptotic activity of AnkG is controlled by p32-mediated intracellular trafficking, which, in turn, seems to be regulated by host cell processes that sense stress.

scholarly journals Mitochondrial Targeting of the Enteropathogenic Escherichia coli Map Triggers Calcium Mobilization, ADAM10-MAP Kinase Signaling, and Host Cell Apoptosis

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Rachana Pattani Ramachandran ◽  
Chaya Spiegel ◽  
Yael Keren ◽  
Tsafi Danieli ◽  
Naomi Melamed-Book ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Membrane Potential ◽  
Mitochondrial Dysfunction ◽  
Host Cell ◽  
Cell Apoptosis ◽  
Mitochondrial Membrane ◽  
Content Type ◽  
Host Cytoplasm ◽  
Host Cell Apoptosis ◽  
Mitogen Activated Protein

ABSTRACT The ability of diarrheagenic bacterial pathogens, such as enteropathogenic Escherichia coli (EPEC), to modulate the activity of mitogen-activated protein kinases (MAPKs) and cell survival has been suggested to benefit bacterial colonization and infection. However, our understanding of the mechanisms by which EPEC modulate these functions is incomplete. In this study, we show that the EPEC type III secreted effector Map stimulates the sheddase activity of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and the ERK and p38 MAPK signaling cascades. Remarkably, all these activities were dependent upon the ability of Map to target host mitochondria, mainly via its mitochondrial toxicity region (MTR). Map targeting of mitochondria disrupted the mitochondrial membrane potential, causing extrusion of mitochondrial Ca2+ into the host cell cytoplasm. We also found that Map targeting of mitochondria is essential for triggering host cell apoptosis. Based on these findings, we propose a model whereby Map imported into mitochondria causes mitochondrial dysfunction and Ca2+ efflux into the host cytoplasm. Since Ca2+ has been reported to promote ADAM10 activation, the acute elevation of Ca2+ in the cytoplasm may stimulate the ADAM10 sheddase activity, resulting in the release of epidermal growth factors that stimulate the ERK signaling cascade. As p38 activity is also Ca2+ sensitive, elevation in cytoplasmic Ca2+ may independently also activate p38. We hypothesize that Map-dependent MAPK activation, combined with Map-mediated mitochondrial dysfunction, evokes mitochondrial host cell apoptosis, potentially contributing to EPEC colonization and infection of the gut. IMPORTANCE Enteropathogenic E. coli (EPEC) is an important human diarrhea-causing bacterium. The pathogenic effects of EPEC largely depend upon its ability to inject a series of proteins, termed effectors, into the host cells. One such effector is the mitochondrion-associated protein (Map). Map has been shown to induce actin-rich projections (i.e., filopodia) on the infected cell surface and activate a Rho GTPase enzyme termed Cdc42. Nonetheless, although most injected Map localizes to host mitochondria, its functions in the mitochondria remain unknown. Here, we show that Map targeting of mitochondria stimulates the disruption of mitochondrial membrane potential to induce Ca2+ efflux into the host cytoplasm. The efflux stimulates the activity of a protein termed ADAM10, which induces activation of a mitogen-activated protein kinase cascade leading to host cell apoptosis. As apoptosis plays a central role in host-pathogen interactions, our findings provide novel insights into the functions of mitochondrial Map in promoting the EPEC disease.

scholarly journals The ZIKA Virus Controls Cell Death through the Anti-Apoptotic Bcl-2 Family Proteins

2019 ◽  
Author(s):  
Jonathan Turpin ◽  
Etienne Frumence ◽  
Philippe Desprès ◽  
Wildriss Viranaïcken ◽  
Pascale Krejbich-Trotot
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Zika Virus ◽  
Congenital Defects ◽  
Host Cell Apoptosis ◽  
Family Protein ◽  
Global Concern ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Replicon Type

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to cause severe complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to control programmed cell death whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

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