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Title: Role for A-Type Lamins in Herpesviral DNA Targeting and Heterochromatin Modulation}
Article:
Abstract:
Posttranslational modification of histones is known to regulate chromatin structure and transcriptional activity, and the nuclear lamina is thought to serve as a site for heterochromatin maintenance and transcriptional silencing. In this report, we show that the nuclear lamina can also play a role in the downregulation of heterochromatin and in gene activation. Herpes simplex virus DNA initiates replication in replication compartments near the inner edge of the nucleus, and histones are excluded from these structures. To define the role of nuclear lamins in HSV replication, we examined HSV infection in wild-type and A-type lamin–deficient( Lmna−/−) murine embryonic fibroblasts( MEFs). In Lmna−/− cells, viral replication compartments are reduced in size and fail to target to the nuclear periphery, as observed in WT cells. Chromatin immunoprecipitation and immunofluorescence studies demonstrate that HSV DNA is associated with increased heterochromatin in Lmna−/− MEFs. These results argue for a functional role for A-type lamins as viral gene expression, DNA replication, and growth are reduced in Lmna−/− MEFs, with the greatest effect on viral replication at low multiplicity of infection. Thus, lamin A/C is required for targeting of the viral genome and the reduction of heterochromatin on viral promoters during lytic infection. The nuclear lamina can serve as a molecular scaffold for DNA genomes and the protein complexes that regulate both euchromatin and heterochromatin histone modifications.
Introduction:
Herpes simplex virus( HSV) undergoes productive infection through transcription and replication of its viral genome within the nucleus[1]. HSV gene expression involves the temporal expression of immediate-early( IE), early( E), and( L) genes[2] and the sequential remodeling of the infected cell nucleus by viral proteins[3]. One of the earliest demonstrations of the compartmentalization of nuclear processes, such as DNA replication, was the observation of replication compartment formation in the nuclei of HSV-infected cells. HSV replication compartments are the site of viral DNA replication, late gene transcription, and viral DNA encapsidation[4]. Replication compartments and parental genome complexes form at the nuclear periphery during early times of infection[4]–[6]. Furthermore, lamin A/C and the nuclear envelope emerin protein co-precipitated with the HSV DNA replication protein ICP8 in a proteomics study[7], suggesting an association of the replication compartment with the nuclear lamina and/or nuclear envelope. The nuclear lamina is disrupted at late times postinfection[8],[9], at least in part to allow access of the nucleocapsids to the inner nuclear envelope for budding and primary envelopment. However, nothing is known about the role of the nuclear lamina at early times postinfection. A-type and B-type lamins are major components of the nuclear lamina that underlies the inner nuclear membrane and provides structural integrity to the nucleus[10]. The A-type lamins( lamins A, C, AD10, and C2) are expressed in differentiated cells and are encoded by the LMNA gene, whose products are encoded by transcripts generated by alternative splicing[11]. A-type lamins are found along the inner side of the nuclear envelope and within the nucleoplasm where they form a veil-like structure[12],[13]. Lamins are believed to function in higher order chromatin organization by acting as part of a molecular scaffold with integral membrane proteins to tether peripheral heterochromatin and chromatin remodeling complexes to the nuclear envelope[14],[15]. Evidence of lamin A/C function in chromatin organization has been provided by studies showing that mutations in the human LMNA gene lead to premature aging and progressive loss of heterochromatin[16],[17], indicating a role for the nuclear lamina in heterochromatin maintenance. Furthermore, immortalized mouse embryonic fibroblasts from Lmna−/− knockout mice exhibit alterations in nuclear envelope integrity, mislocalization of lamin binding proteins, and reduced peripheral heterochromatin[18],[19]. Targeting of genes to the nuclear periphery has been associated with gene silencing in several cases[20],[21]; however, in other cases the movement of active genes to the periphery is believed to be due to association of actively transcribing genes with nuclear pores[22],[23] and not the nuclear lamina. Hence, the role of nuclear targeting in regulation of gene expression remains to be fully defined. The available data suggest a role for the nuclear lamina in maintenance of heterochromatin and gene silencing. Viruses have served as sensitive probes for the study of mechanisms of cellular processes, and chromatin plays an important role in regulation of HSV gene expression[24]. HSV DNA in the virion is not associated with histones[25]. As DNA enters the nucleus, cellular mechanisms attempt to silence the incoming genome through assembly of heterochromatin onto the DNA molecules, as first observed in transfected cells[26]. The HSV VP16 tegument protein plays a role in reducing histone association with viral DNA and in increasing the euchromatin modifications on the histones associated with viral genes[27],[28]. The HSV immediate-early( IE) ICP0 protein acts as an inhibitor of histone deacetylases[28]–[30]. In terms of the cellular mechanisms regulating chromatin structure, little is known about the nuclear location where chromatin modification takes place or is regulated beyond the role of the nuclear lamina in heterochromatin maintenance. This study provides evidence that lamin-dependent targeting of the HSV genome to the nuclear periphery is associated with a reduction of heterochromatin on viral lytic genes.
Discussion:
We have demonstrated that the type A lamins are required for targeting of the HSV genome to the nuclear periphery for assembly of the early replication compartments, as shown previously at early times of infection[4] and in cells along the edge of a plaque[5],[6]. Localization to the nuclear periphery is correlated with reduced levels of heterochromatin on viral IE gene promoters, arguing that viral DNA located at the nuclear periphery is protected from chromatin silencing by the host cell machinery. The HSV VP16 virion protein and the ICP0 IE protein have been shown to play roles in promoting the acetylation of histone H3 on HSV DNA. ICP0 is not required for localization of viral genomes to the nuclear periphery[6], but there is no information about VP16 as yet. Thus, the viral and cellular proteins involved in tethering HSV DNA on the nuclear periphery remain to be defined. Also, the stage in viral replication at which the HSV genome associates with the nuclear lamina or nuclear periphery is not known. Association of the viral genome with the nuclear lamina could occur at the time of IE gene transcription, E gene transcription or initiation of viral DNA replication, although our data and those of others[6] argue that this may occur at or before IE gene transcription. Replication of the genomes of RNA viruses in the cytoplasm has also been proposed to occur on a surface but in that case on membranes( reviewed in[36]). Thus, nuclear DNA viruses may use the nuclear lamina and inner nuclear envelope as a platform for replication while cytoplasmic RNA viruses use cytoplasmic membranes as a platform for replication. It has been proposed that these surfaces provide a two-dimensional lattice or platform for assembly of replication complexes[37]. The nuclear lamina may play an additional role in providing a platform for recruitment of viral DNA as well as chromatin-modifying enzymes that keep the viral genome in an active chromatin conformation. We found that the requirement for lamin A by HSV replication was multiplicity-dependent in that the reduction of replication in Lmna−/− cells was about 5-fold at high MOI( 10 PFU/cell) while at low MOI( 0. 01 PFU/cell), the reduction in Lmna−/− cells was approximately 100-fold. Defects in replication compartment formation and heterochromatin association with replication compartments were observed under both conditions; thus, we believe that A-type lamins exert similar effects on viral replication at low and high MOI. At high MOI, however, the virus can circumvent the heterochromatin block. It is conceivable that at high MOI the large number of input viral genomes titrates out the finite amount of histones in the infected cell and the genomes are transcribed. Alternatively, at high MOI, the increased numbers of viral genomes eventually encounter histone-modification enzymes by less efficient means than in the assemblies located on the nuclear lamina. It is worth noting that the replication requirement for ICP0, which inhibits histone deacetylases[38], is also multiplicity-dependent[39],[40]. Therefore, the viral and cellular functions that HSV uses to prevent chromatin silencing appear to be more important at lower MOI's. Previous studies have largely documented a role for the A type lamins in maintenance of heterochromatin. Mutations in the human LMNA gene lead to premature aging and progressive loss of heterochromatin[16],[17], while immortalized mouse embryonic fibroblasts from Lmna−/− knockout mice exhibit alterations in nuclear envelope integrity, mislocalization of lamin-binding proteins, and reduced peripheral heterochromatin[18],[19]. In contrast, our results argue that type A lamins are necessary for preventing assembly or for removal of heterochromatin on HSV IE genes during lytic infection. Although these results may seem to be inconsistent, we propose that lamin A can serve as a platform for the organization of enzyme complexes that, under the appropriate conditions, can lead to heterochromatin or euchromatin formation on DNA sequences associated with the lamina. We further hypothesize that during HSV lytic infection viral gene products act to shift the balance towards euchromatin through the assembly of chromatin and enzyme complexes on viral lytic genes associated with the nuclear lamina that lead to euchromatic modifications of histones. In contrast, during latent infection the HSV latency-associated transcript promotes the assembly of heterochromatin on viral DNA during latent infection[34]. Thus, by regulating the type of chromatin on the viral chromosome, HSV determines whether it will undergo a productive or latent infection in different cell types. Further studies should determine the precise mechanism by which the nuclear lamins are exploited by HSV to keep its genome transcriptionally active during productive infection. These studies should provide the basis for mechanisms operative on cellular chromatin as well.
Transcription of eukaryotic genes is regulated by sequence-specific DNA-binding proteins that bind to the DNA as well as the structure of the chromatin associated with the specific gene . Posttranslational modification of histones plays a major role in the higher order structure of the chromatin and whether it serves as heterochromatin or inactive chromatin versus euchromatin or active chromatin . The nuclear lamina has been shown to promote the maintenance of heterochromatin in mammalian cells , but little is known about where heterochromatin is modulated . In this study , we find that the A-type lamins are required for the targeting of herpes simplex virus genomic DNA to the periphery of the infected cell nucleus and for the prevention or reduction of heterochromatin on the viral genome and transcriptional silencing of the viral genome . This raises the broader function of the nuclear lamina in the regulation of both euchromatin and heterochromatin . We propose that the nuclear lamina is a platform for the organization of chromatin remodeling and histone modification enzymes that regulate both euchromatin and heterochromatin .