A novel checkpoint in the Bcl-2–regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells

Andoniou, Christopher E.; Andrews, Daniel M.; Manzur, Mitali; Ricciardi‐Castagnoli, Paola; Degli-Esposti, Mariapia A.

doi:10.1083/jcb.200403010

Cited by 26 publications

(27 citation statements)

References 57 publications

(101 reference statements)

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“…15,34,35 It is possible that viruses may contain proteins to target both Bak and Bax, depending on their host range or tissue specificity. Consistent with this hypothesis, Andoniou et al 36 have recently suggested that mouse cytomegalovirus encodes proteins in addition to vMIA that specifically interfere with Bak function. Interestingly, the region of F1L that we have shown to interact with Bak exhibits only limited homology to cellular or viral BH3 domains, yet it specifically binds Bak (Figures 4 and 6).…”

Section: F1l Binds Bak To Inhibit Apoptosismentioning

confidence: 58%

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

et al. 2006

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Apoptosis represents an important cellular defence mechanism against viral pathogens by virtue of its ability to remove infected cells. Consequently, many viruses have developed numerous strategies to prevent or delay host cell apoptosis in order to achieve productive replication. Here we report that deletion of the F1L gene from the vaccinia genome results in increased apoptosis during infection. We demonstrate that F1L, which has no sequence homology to Bcl-2 family members, inhibits apoptosis at the level of mitochondria by binding to Bak. As a consequence, F1L prevents Bak activation, oligomerization and interaction with active Bax, all critical steps in the induction of apoptosis. We demonstrate that residues 64-84 of F1L interact directly with the Bcl-2 homology domain 3 (BH3) domain of Bak. This region of F1L has limited sequence similarity to known Bak-interacting BH3 domains. We also find that such additional BH3-like domains exist in the vaccinia genome. We conclude that F1L uses this specific, BH3-like domain to bind and inhibit Bak at the mitochondria.

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Section: F1l Binds Bak To Inhibit Apoptosismentioning

confidence: 58%

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

et al. 2006

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“…Thus, m38.5 appears to selectively inhibit Bax-dependent apoptosis. MCMV infection induces the oligomerization of both Bax and Bak while also inhibiting apoptosis (1). In contrast, the transient transfection of m38.5 into HeLa cells does not induce detectable Bak oligomerization upon cross-linking with bismaleimidohexane (data not shown).…”

Section: Discussionmentioning

confidence: 79%

Cytomegalovirus Proteins vMIA and m38.5 Link Mitochondrial Morphogenesis to Bcl-2 Family Proteins

Norris

Youle

2008

J Virol

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Apoptosis is a host defense mechanism against viruses that can be subverted by viral gene products. Human cytomegalovirus encodes viral mitochondria-localized inhibitor of apoptosis (vMIA; also known as pUL37x1), which is targeted to mitochondria and functions as a potent cell death suppressor by binding to and inhibiting proapoptotic Bcl-2 family members Bax and Bak. vMIA expression also dramatically alters mitochondrial morphology, causing the fragmentation of these organelles. A potential ortholog of vMIA, m38.5, which was identified in murine cytomegalovirus, has been shown to localize to mitochondria and protect against chemically induced apoptosis by unknown mechanisms. Despite sharing negligible homology with vMIA and no region detectably corresponding to the vMIA Bax-binding domain, we find that m38.5, like vMIA, binds to Bax and recruits Bax to mitochondria. Interestingly, m38.5 and vMIA appear to block Bax downstream of translocation to mitochondria and after an initial stage of Bax conformational change. In contrast to vMIA, m38.5 neither binds to Bak nor causes mitochondrial fragmentation. Consistently with Bax-selective inactivation by m38.5, m38.5 fragments mitochondria in Bak knockout (KO) cells and protects Bak KO cells from apoptosis better than Bax KO cells. Thus, vMIA and m38.5 share some, but not all, features of apoptosis regulation through Bcl-2 family interaction and allow the dissection of Bax translocation into discrete steps.

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“…Unlike EBV and KSHV, HCMV does not encode a viral homolog of Bcl-2 (43,44). Instead, HCMV encodes vMIA, a potent viral mitochondrial inhibitor of apoptosis expressed during lytic infection (45-47) which is not synthesized in persistently infected monocytes (Fig.…”

mentioning

confidence: 99%

BH3 Profiling Reveals Selectivity by Herpesviruses for Specific Bcl-2 Proteins To Mediate Survival of Latently Infected Cells

Cojohari

Burrer

Peppenelli

et al. 2015

J Virol

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Herpesviruses, including human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus, establish latency by modulating or mimicking antiapoptotic Bcl-2 proteins to promote survival of carrier cells. BH3 profiling, which assesses the contribution of Bcl-2 proteins towards cellular survival, was able to globally determine the level of dependence on individual cellular and viral Bcl-2 proteins within latently infected cells. Moreover, BH3 profiling predicted the sensitivity of infected cells to small-molecule inhibitors of Bcl-2 proteins.

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A novel checkpoint in the Bcl-2–regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells

Cited by 26 publications

References 57 publications

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis

Cytomegalovirus Proteins vMIA and m38.5 Link Mitochondrial Morphogenesis to Bcl-2 Family Proteins

BH3 Profiling Reveals Selectivity by Herpesviruses for Specific Bcl-2 Proteins To Mediate Survival of Latently Infected Cells

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