Critical Role for Antiapoptotic Bcl-xL and Mcl-1 in Human Macrophage Survival and Cellular IAP1/2 (cIAP1/2) in Resistance to HIV-Vpr-induced Apoptosis

Busca, Aurelia; Saxena, Mansi; Kumar, Ashok

doi:10.1074/jbc.m111.312660

Cited by 71 publications

(108 citation statements)

References 62 publications

(77 reference statements)

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“…However, unlike GM-CSF and M-CSF that simply block the first of two proteolytic cleavage steps required for the full activation of caspase 3, HCMV infection induces Mcl-1 and HSP27 to block both cleavages, suggesting a critical role of these two proteins in the early HCMVinduced prosurvival state (14,17). Indeed, M-CSF treatment does not increase expression of Mcl-1 or HSP27 until 5 to 7 days posttreatment (27,31), indicating that the simultaneous and rapid induction of both antiapoptotic regulators may be unique to HCMV infection. In accordance with Mcl-1 and HSP27 acting as late survival proteins during M-CSF-induced differentiation, we found Mcl-1 and HSP27 expression to be increased by 24 hpi in HCMV-infected but not M-CSF-treated monocytes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Transcriptome studies also showed increased HSP27 expression to be regulated in a PI3K-dependent manner (30). However, despite also rapidly activating PI3K, M-CSF treatment does not increase expression of Mcl-1 and HSP27 until 5 and 7 days posttreatment, respectively, suggesting that a unique regulation of the PI3K pathway by HCMV during viral entry may promote the expression of select antiapoptotic proteins (27,31). Akt (the downstream target of PI3K) substrate specificity is regulated by the phosphorylation ratio of two phosphorylation sites, indicating that upstream signaling events are key determinants to the functional outcome of PI3K signaling (32,33).…”

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confidence: 99%

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Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

Peppenelli

Arend

Cojohari

et al. 2016

J Virol

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Primary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. To facilitate viral spread, we have previously shown HCMV to extend the short 48-h life span of monocytes. Mechanistically, HCMV upregulated two specific cellular antiapoptotic proteins, myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the two proteolytic cleavages necessary for the formation of fully active caspase 3 and the subsequent initiation of apoptosis. We now show that HCMV more robustly upregulated Mcl-1 than normal myeloid growth factors and that Mcl-1 was the only myeloid survival factor to rapidly induce HSP27 prior to the 48-h cell fate checkpoint. We determined that HCMV glycoproteins gB and gH signal through the cellular epidermal growth factor receptor (EGFR) and ␣v␤3 integrin, respectively, during viral entry in order to drive the increase of Mcl-1 and HSP27 in an Akt-dependent manner. Although Akt is known to regulate protein stability and transcription, we found that gB-and gH-initiated signaling preferentially and cooperatively stimulated the synthesis of Mcl-1 and HSP27 through mTOR-mediated translation. Overall, these data suggest that the unique signaling network generated during the viral entry process stimulates the upregulation of select antiapoptotic proteins allowing for the differentiation of short-lived monocytes into long-lived macrophages, a key step in the viral dissemination strategy. H uman cytomegalovirus (HCMV), a betaherpesvirus, is highly prevalent throughout the United States, with 50 to 80% of the population being seropositive (1). HCMV infection is generally asymptomatic in immunocompetent individuals although infection has been linked to chronic inflammatory diseases, such as atherosclerosis and acute infection mononucleosis (2, 3). In contrast, HCMV infection causes significant morbidity and mortality in immunocompromised individuals, including AIDS patients, neonates, and transplant recipients (4-6). In these patients, HCMV diseases are diverse with respect to the organ site, including eyes (retinitis), brain (encephalopathy), central nervous system (polyradiculopathy), lungs (pneumonitis), and gastrointestinal tract (gastroenteritis), which can lead to systemic organ failure (7,8). The systemic pathogenesis established by HCMV is dependent on the spread of the virus from the initial point of infection to peripheral organs. IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic within the human population. Although primary infection is generally asymptomatic in immunocompetent individualsMonocytes are believed to be the primary cell type responsible for the systemic dissemination of HCMV during both symptomatic and asymptomatic infections (9-11). However, monocytes have a limited life span of 48 h following release from the bone marrow, after which these cells either undergo apoptosis or differentiate into long-lived macrophages in the presence of a differentiation stimulus (1...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

Peppenelli

Arend

Cojohari

et al. 2016

J Virol

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“…Additionally, mature macrophages express MCL-1 in an AKT-dependent but NF-jB-independent manner [93]. siRNA-mediated downregulation of BCL-XL or MCL-1 in human monocyte-derived macrophages or THP1-MACs resulted in their increased cell death, indicating that both proteins are important for maintaining survival of human macrophages under homeostatic conditions [94].…”

Section: Myelopoiesismentioning

confidence: 99%

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

et al. 2016

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Members of the Bcl‐2 protein family regulate cell fate decisions following a variety of developmental cues or stress signals, with the outcomes of cell death or survival, thus shaping multiple mammalian tissues. This review describes in detail how anti‐ and proapoptotic Bcl‐2 proteins contribute to the development and functioning of the fetal and adult hematopoietic systems and how they influence the generation and maintenance of different hematopoietic lineages. An overview on how stress signals such as genotoxic stress or inflammation can compromise blood cell production, partially by engaging the intrinsic apoptosis pathway, is presented. Finally, the review describes how Bcl‐2 protein deregulation—either leading to increased apoptosis resistance or excessive cell death—contributes to many hematological disorders, with specific focus on rare disorders of hematopoiesis and how this knowledge may be used therapeutically.

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“…In contrast to the p53-dependent induction of proapoptotic genes, this cluster contained two genes, BIRC3 and TNFAIP3, encoding antiapoptotic proteins. Baculoviral IAP repeat-containing 3 (BIRC3) is an E3 ubiquitin ligase that targets caspase 3 and caspase 7 and the TNF receptor-associated factors TRAF1 and TRAF2, accounting for BIRC3-mediated inhibition of apoptotic signals (38,39). TNFa-induced protein 3 (TNFAIP3) protects cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD [TNF receptor superfamily 1A (TNFRSF1A)-associated death domain] and the kinase RIP (receptorinteracting protein) to the TNF receptor signaling complex (40,41).…”

Section: The Nf-kb Component Of the Ir Responsementioning

confidence: 99%

Parallel Profiling of the Transcriptome, Cistrome, and Epigenome in the Cellular Response to Ionizing Radiation

et al. 2014

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The DNA damage response (DDR) is a vast signaling network that is robustly activated by DNA double-strand breaks, the critical lesion induced by ionizing radiation (IR). Although much of this response operates at the protein level, a critical component of the network sustains many DDR branches by modulating the cellular transcriptome. Using deep sequencing, we delineated three layers in the transcriptional response to IR in human breast cancer cells: changes in the expression of genes encoding proteins or long noncoding RNAs, alterations in genomic binding by key transcription factors, and dynamics of epigenetic markers of active promoters and enhancers. We identified protein-coding and previously unidentified noncoding genes that were responsive to IR, and demonstrated that IR-induced transcriptional dynamics was mediated largely by the transcription factors p53 and nuclear factor κB (NF-κB) and was primarily dependent on the kinase ataxia-telangiectasia mutated (ATM). The resultant data set provides a rich resource for understanding a basic, underlying component of a critical cellular stress response.

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Critical Role for Antiapoptotic Bcl-xL and Mcl-1 in Human Macrophage Survival and Cellular IAP1/2 (cIAP1/2) in Resistance to HIV-Vpr-induced Apoptosis

Cited by 71 publications

References 62 publications

Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

Parallel Profiling of the Transcriptome, Cistrome, and Epigenome in the Cellular Response to Ionizing Radiation

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