Intermediate filaments, actin-containing microfilaments and microtubules are the three main cytoskeletal systems of vertebrate and many invertebrate cells. Although these systems are composed of distinctly different proteins, they are in constant and intimate communication with one another. Understanding the molecular basis of this cytoskeletal crosstalk is essential for determining the mechanisms that underlie many cell-biological phenomena. Recent studies have revealed that intermediate filaments and their associated proteins are important components in mediating this crosstalk.
Recent evidence showing that intermediate filaments (IFs) are dynamic, motile elements of the cytoskeletal repertoire of vertebrate cells has overturned the long-standing view that they simply form static `space filling' cytoplasmic networks. In fact, many types of IF are now known to engage in a remarkable array of movements that are closely associated with their assembly, disassembly and subcellular organization. Some of these motile properties are intrinsic to IFs and others are attributable to molecular crosstalk with either microtubules or actin-containing microfilaments. This crosstalk is, to a large extent, mediated by molecular motors, including conventional kinesin and cytoplasmic dynein. These motors are responsible for the high-speed delivery of nonfilamentous IF precursors and short filaments to specific regions of the cytoplasm, where they assemble into long IFs. Interestingly, the patterns and speeds of IF movements vary in different cell types and even within different regions of the same cell. These differences in motility may be related to their interactions with different types of molecular motor and/or other factors, such as IF-associated proteins.
The role of the intranuclear movement of chromatin in gene expression is not well-understood. Herpes simplex virus forms replication compartments (RCs) in infected cell nuclei as sites of viral DNA replication and late gene transcription. These structures develop from small compartments that grow in size, move, and coalesce. Quantitative analysis of RC trajectories, derived from 4D images, shows that most RCs move by directed motion. Directed movement is impaired in the presence of actin and myosin inhibitors as well as a transcription inhibitor. In addition, RCs coalesce at and reorganize nuclear speckles. Lastly, distinct effects of actin and myosin inhibitors on viral gene expression suggest that RC movement is not required for transcription, but rather, movement results in the bridging of transcriptionally active RCs with nuclear speckles to form structures that enhance export of viral late mRNAs.gene movement | nuclear export M ovement of chromatin and its interactions and location in the nucleus are believed to be important for regulation of gene expression (1). A number of studies have shown an association between the movement of chromosomal domains and changes in transcriptional activity. In yeast, activation of genes is associated with targeting of the gene to the nuclear periphery (2, 3), and this is believed to be because of the linkage of actively transcribed genes to the nuclear pore complex for RNA export (4). Lymphoid cell genes move to positions near centromeric heterochromatin coincident with transcriptional silencing (5). Transcriptional activation of the β-globin locus involves movement of the gene away from centromeric heterochromatin (6). During B-cell development, the IgH and Igκ loci are localized at the nuclear periphery in hematopoietic progenitor cells, but they move internally coincident with transcriptional activation in pro-B cells (7). Similarly, the β-globin gene relocalizes to the nuclear interior as it is activated during murine erythroid differentiation (8). Actively transcribed genes are also thought to be brought into close contact with nuclear speckles (9, 10), sites often regarded as hubs of RNA metabolism. Although these results link gene movement with changes in transcriptional activity, it is unclear whether intranuclear movement of chromatin is the cause or result of changes in transcriptional activity (1). Therefore, it is important to define systems in which the function of chromatin movement can be experimentally assessed.Nuclear forms of actin and myosin have been implicated in mediating long-range directed movement (11-13), but the mechanism by which this putative nucleoskeletal system operates is unknown. In addition to their possible roles in mediating intranuclear movement, there is increasing evidence for roles of nuclear actin and myosin in cellular transcription, chromatin remodeling, and mRNA export (reviewed in ref. 14). How and whether their roles in movement are connected to regulation of gene activity are unclear.Viruses are simple genetic entities and ha...
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.
For many years, cytoplasmic intermediate filaments (IFs) were considered to be stable cytoskeletal elements contributing primarily to the maintenance of the structural and mechanical integrity of cells. However, recent studies of living cells have revealed that IFs and their precursors possess a remarkably wide array of dynamic and motile properties. These properties are in large part due to interactions with molecular motors such as conventional kinesin, cytoplasmic dynein, and myosin. The association between IFs and motors appears to account for much of the well-documented molecular cross talk between IFs and the other major cytoskeletal elements, microtubules, and actin-containing microfilaments. Furthermore, the associations with molecular motors are also responsible for the high-speed, targeted delivery of nonfilamentous IF protein cargo to specific regions of the cytoplasm where they polymerize into IFs. This review considers the functional implications of the motile properties of IFs and discusses the potential relationships between malfunctions in these motile activities and human diseases.
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