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Title: Bim Nuclear Translocation and Inactivation by Viral Interferon Regulatory Factor}
Article:
Abstract:
Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8( HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors( vIRFs 1–4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFβ receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, co-localization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication-induced apoptosis and suggest that inhibitory targeting of vIRF-1:Bim interaction may provide an effective antiviral strategy.
Introduction:
Human herpesvirus 8( HHV-8) is associated with the endothelial tumor Kaposi's sarcoma in addition to the B cell malignancies primary effusion lymphoma( PEL) and multicentric Castleman's disease[1]–[3]. Several genes, including vIRF-1, have been noted to have oncogenic capacity in culture and in in vivo models[4],[5]. However, most of these genes are expressed during productive, lytic replication, suggesting that they do not play direct roles in malignant pathogenesis, but rather serve to enhance virus production. Oncogenic properties such as promotion of proliferative signaling pathways and cell survival are indeed consistent with putative roles in establishing conditions that are conducive to virus productive replication. For example, the viral IRFs function to block innate cellular responses of cell cycle arrest and apoptosis that would be induced by virus replication[6]–[8], and these properties, functioning normally to promote virus replication, could also be pro-oncogenic in experimental systems. Of note is that vIRF-1 can bind to and inhibit interferon-activated apoptotic effector proteins such as p53 and GRIM19[( gene for) retinoid-IFN-induced mortality 19] in addition to p53-activating ATM[9]–[11]. In contrast to investigations of pro-survival and pro-tumorigenic activities of the vIRFs, studies of the functions of these proteins in normal virus biology, and in particular their roles during lytic replication, are lacking, although it is speculated that they do indeed function to enhance virus production by countering innate cellular defenses. Previous studies from this laboratory noted the importance of the pro-apoptotic BH3-only protein Bim in negative regulation of HHV-8 productive replication in endothelial cells[12]. The viral chemokines vCCL-1 and vCCL-2 were found to induce signal transduction in endothelial cells leading to the repression of Bim induction following starvation-mediated stress and to promote virus replication, effected via both endogenously produced and exogenously added v-chemokines. The central relevance of Bim to productive replication of HHV-8 was indicated more directly by the demonstration that HHV-8 production was massively increased in cells depleted of Bim via shRNA transduction[12]. In this system, the positive effects of vCCL-1 and vCCL-2 were abrogated, suggesting that these viral chemokines exert pro-replication effects via control of lytic cycle-induced Bim expression, thereby acting to inhibit apoptosis and allow a window for virus production. Bim is induced by a number of stress factors, such as nutrient deprivation, growth factor withdrawal, U. V. irradiation and anti-tumor drugs, in addition to stress induced by virus replication[13]. The classical model of Bim activation is via JNK-mediated phosphorylation, of long( BimL) and extra-long( BimEL) splice-isoforms of Bim, and consequent release from dynein-motor complexes, allowing translocation of the BH3-only protein to mitochondria[14],[15]. Disruption of Bim-cytoskeletal sequestration can also be mediated via induction of Gadd45, regulated by p53 and a mediator of cell cycle arrest and apoptosis[16]; Gadd45 may promote Bim release in part through activation of JNK kinase MEKK4. At mitochondria, Bim triggers apoptosis via interactions with anti-apoptotic Bcl-2 proteins to relieve suppression of Bax/Bak apoptotic effector oligomerization and pore formation in mitochondrial membranes. In addition to cytoplasmic sequestration via dynein motor association, negative regulation of BimEL can be effected by AKT and ERK phosphorylation, leading to 14-3-3 cytosolic sequestration and proteasomal degradation of Bim, respectively[17]–[19]. The short isoform of Bim, BimS, lacks all phosphorylation sites( JNK, AKT and ERK targets) and therefore cannot be regulated like its larger counterparts. However, in contrast to these proteins, expression of BimS appears to be highly restricted in vivo, and its precise role remains unclear[20],[21]. Here we identify a novel mechanism of Bim inactivation, via nuclear sequestration, mediated by HHV-8 vIRF-1. The data presented suggest that disruption of such regulation could provide a unique and useful means of controlling HHV-8 productive replication.
Discussion:
HHV-8 encoded viral interferon regulatory factors have been noted previously to interfere with innate immune responses of cells, in particular via their inhibition of activities of cellular IRFs, necessary for interferon induction and consequent cell cycle arrest and apoptosis[6],[8]. vIRF-1 has been reported to interact with a broad range of proteins in addition to cellular IRFs; these other proteins include p53, ATM, TGFβ-activated Smad transcription factors, and GRIM19[25],[9],[10],[26], all of which play roles in mediating innate immune functions via regulation of cell cycle and apoptosis. These activities, induced by infection, presumably must be controlled sufficiently by the virus to allow productive replication in the face of stress signaling. Bim, induced strongly and rapidly following HHV-8 lytic reactivation in latently infected endothelial cells, is a powerful inhibitor of HHV-8 production in this cell type and thus represents a biologically relevant target of vIRF-1[12]. The data presented here indicate that vIRF-1:Bim interaction is indeed important in the context of virus replication, being necessary for substantial or major proportions of replication-enhancing and anti-apoptotic activities specified by vIRF-1 in lytically reactivated endothelial cells. Thus, vIRF-1 regulation of Bim pro-apoptotic function represents a critical component of vIRF-1 activity and one which is essential for normal virus productive replication, at least in this cell type. To our knowledge, this is the first demonstration of interaction between an IRF homologue and a member of the Bcl-2 family, and the first report of nuclear translocation of Bim or any other Bcl-2 related protein as a means of functional inactivation. Whether physiological conditions unconnected with viral infection can promote such nuclear localization and inactivation is unclear; none has been reported to date. On the other hand, several previous investigations have noted the nuclear localization and functions of Bcl-2 family members. Bcl-2 nuclear localization can occur during oxidative stress, Bcl-2 overexpression or loss of interaction with mitochondrial-localizing protein FKBP38, with promotion of apoptosis via blocking of nuclear trafficking of transcription factors[28]–[31]. Mcl-1 has been reported to inhibit cell proliferation via inhibitory interactions with proliferating cell nuclear antigen and cyclin-dependent kinase 1[32]–[34], whereas the Bcl-2-related protein Bok, which cannot heterodimerize with Bcl-2 or Bcl-xL, can localize to and function in the nucleus to promote apoptosis[35]. A splice variant of Bfl-1, Bfl-1S, in which mitochondrial-localizing hydrophobic C-terminal sequences are replaced with a basic nuclear-localization signal, may mediate anti-apoptotic activity via nuclear sequestration of components of the apoptotic cascade[36]. Nuclear-localized pro-death activity of apoptotic effector Bax has been proposed due to correlation of Bax nuclear translocation in response to alkylating agent( BCNU) with glioma cell sensitivity to the apoptotic inducer[37]. Thus, while there is prior evidence of nuclear localization of Bcl-2 family proteins, both pro- and anti-apoptotic, along with evidence of function in this compartment, the induced nuclear localization and inactivation of BH3-only protein Bim identified here appears to be unique and the first example of viral control of apoptosis via nuclear sequestration of a Bcl-2 family member. That a viral IRF homologue mediates this effect is also a novel finding. Our demonstration that vIRF-1:Bim interaction is both important for virus productive replication and can be inhibited via peptide-mediated disruption suggests that targeting vIRF-1:Bim interaction may provide a useful antiviral strategy.
Human herpesvirus 8 ( HHV-8 ) is a pathogen associated with cancers Kaposi's sarcoma ( KS ) , an endothelial cell disease , and B cell malignancies primary effusion lymphoma and multicentric Castleman's disease . KS is particularly prevalent amongst HIV-positive populations in Africa and is a major health concern . Virus productive replication , in addition to latency , is important for maintaining viral load within the host and also for KS pathogenesis . Essential to HHV-8 and other virus replication is the control of innate host defenses , which comprise stress-sensing cellular signaling pathways that result ultimately in programmed cell death ( apoptosis ) . Here we identify a novel mechanism whereby a viral protein , viral interferon regulatory factor-1 ( vIRF-1 ) , mediates inhibition of a stress sensor and initiator of apoptosis , Bim , by inducing its translocation to the cell nucleus and thereby sequestration away from the cytoplasmic compartment where it exerts its pro-death activity . We show that vIRF-1:Bim interaction is necessary for efficient HHV-8 productive replication and that it can be blocked using a cell-permeable antagonist of vIRF-1:Bim binding . Our data not only identify previously unsuspected mechanisms of Bim inactivation and vIRF-1 function , but suggest that inhibitory targeting of vIRF-1 interaction with Bim may be of therapeutic benefit .