The nuclear envelope has long been a focus of basic research for a highly specialized group of cell biologists. More recently, an expanding group of scientists and physicians have developed a keen interest in the nuclear envelope since mutations in the genes encoding lamins and associated proteins have been shown to cause a diverse range of human diseases often called laminopathies or nuclear envelopathies. Most of these diseases have tissue-selective phenotypes, suggesting that the nuclear envelope must function in cell-type- and developmental-stage-specific processes such as chromatin organization, regulation of gene expression, controlled nucleocytoplasmic transport and response to stress in metazoans. On 22–23 April 2009, Professor Christopher Hutchison organized the 4th British Nuclear Envelope Disease and Chromatin Organization meeting at the College of St Hild and St Bede at Durham University, sponsored by the Biochemical Society. In attendance were investigators with one common interest, the nuclear envelope, but with diverse expertise and training in animal and plant cell biology, genetics, developmental biology and medicine. We were each honoured to be keynote speakers. This issue of Biochemical Society Transactions contains papers written by some of the presenters at this scientifically exciting meeting, held in a bucolic setting where the food was tasty and the wine flowed freely. Perhaps at the end of this excellent meeting more questions were raised than answered, which will stimulate future research. However, what became clear is that the nuclear envelope is a cellular structure with critical functions in addition to its traditional role as a barrier separating the nuclear and cytoplasmic compartments in interphase eukaryotic cells.

The nuclear envelope and its link to disease

The nuclear envelope is composed of the nuclear membranes, nuclear pore complexes and nuclear lamina. Each of the nuclear membrane domains, inner, outer and pore, contain unique integral proteins. The pore complexes are large, macromolecular structures through which molecules ranging from ions to proteins and RNA complexes are transported between the nucleus and the cytoplasm. Using proteomics, most of the proteins of the yeast and mammalian nuclear pore complexes [1,2] and rat inner nuclear membrane [3] have been identified, but the specific functions of many of these proteins are still unknown.

The nuclear lamina appears as a fibrous-like structure on the nuclear side of the inner nuclear membrane in electron micrographs [4]. Pioneering work in the laboratory of Günter Blobel in the 1970s and 1980s led to the identification of the lamin proteins, the building blocks of the nuclear lamina [5,6]. Subsequently, the laboratories of Blobel [7] and Marc Kirschner [8] showed by cDNA cloning that the lamins were members of the intermediate filament protein family. At around the same time, Aebi et al. [9] and Goldman et al. [10] showed that the lamina was an intermediate filament meshwork. Later studies identified several integral proteins of the inner nuclear membrane that interact with lamins [11,12]. The lamina and various integral inner nuclear membrane proteins interact with chromatin, and it has been hypothesized that together they are involved in organizing chromatin. Plants, as reviewed by Graumann and Evans [13] in this issue of Biochemical Society Transactions, and yeast do not have structural orthologues of lamins or most animal inner nuclear membrane proteins, although nuclear envelope functions such as the organization of chromatin and others discussed below appear to be conserved.

It is now known that in humans three genes, LMNA, LMNB1 and LMNB2, encode nuclear lamins that can be variably expressed in different cells. LMNA encodes the major somatic cell-specific lamin isoforms, lamin A and lamin C, arising by alternative pre-mRNA splicing [14]. In 1999, Bonne et al. [15] reported that mutations in LMNA cause autosomal dominant Emery–Dreifuss muscular dystrophy, a disease that affects the heart and some skeletal muscles. Since then, geneticists have linked approximately a dozen differentially defined clinical conditions to mutations in LMNA and even more diseases to mutations in other lamin genes and genes encoding other nuclear envelope proteins [16]. In this issue of Biochemical Society Transactions, Scharner et al. [17] clarify some of the genotype–phenotype relationships of diseases caused by mutations in genes encoding nuclear envelope proteins and emphasize that much more remains to be studied in order to understand the underlying disease mechanism. But even based on what we already know, the discoveries linking these diseases to defects in the nuclear envelope have provided novel insights into nuclear envelope cell biology. As most of the different nuclear-envelope-linked diseases, even the ones arising by different mutations in LMNA, affect only certain tissues and organs at different times of life, the nuclear envelope must be involved in regulating tissue-specific and developmental processes. At what levels can this occur?

Chromatin organization

Many groups have hypothesized that the nuclear envelope is involved in organizing chromatin, which is increasingly understood also as a means of regulating gene expression. A logical extension would be that changes in the nuclear envelope during development generate specific tissue differentiation programmes and that abnormalities in the nuclear envelope in disease could lead to pathogenic gene expression programmes. Although this hypothesis is appealing, little solid data have been generated to support it. Two papers in this issue addressed this hypothesis. Elcock and Bridger [18] review data showing that the position within the nucleus affects the expression of certain genes and discuss how the nucleoskeleton could organize the genome in normal and disease states. Malik et al. [19] summarize data showing that genes located at the nuclear periphery tend to be inactive and that genes can be inactivated by being artificially tethered to the nuclear periphery by an affinity mechanism. As Malik et al. [19] emphasize, a next important step will be to identify endogenous nuclear envelope and chromatin proteins that participate in affinity-driven tethering to the nuclear periphery. More challenging could be experiments to show that a change in the positioning of specific genes or groups of genes actually leads to changes in cellular or organism phenotype.

Cell signalling

There is growing evidence that lamins and lamin-binding proteins are involved in the regulation of signalling pathways and transcription factors. The molecular mechanisms of these lamin-mediated regulatory functions are just beginning to emerge, but a few general principles can be deduced from the data available. The nuclear envelope can serve as a scavenger for several components of signalling pathways (c-Fos, Smads) and transcription regulators (Oct1), thereby inhibiting signal specific responses. In addition, lamins at the nuclear lamina and in the nucleoplasm can act as scaffold platforms recruiting synergistically acting signalling molecules of a specific pathway to generate an efficient cell-type- and tissue-specific response. How these scaffolding activities of lamins are regulated is still a mystery. Boban et al. [20] summarize the known regulatory roles of lamins in signalling and gene expression, focusing on pathways that affect cell-cycle progression and differentiation.

Nucleocytoplasmic transport

Several inherited diseases have recently been linked to mutations in genes encoding nuclear pore complex proteins. As the lamina and pore complexes can be isolated as a single structure and are presumably connected in cells [5], disease-causing abnormalities in the lamina could also potentially affect pore complex function. However, surprising little attention has been focused on how nucleocytoplasmic transport could be affected by structural or compositional changes in the nuclear envelope. Perhaps this is because little is known about how nuclear pore complex composition varies in different cell types and possibly in disease states. Furthermore, very little is known about how the nuclear pore complex is organized structurally to facilitate diverse transport routes. Using yeast as a model system, Fiserova and Goldberg [21] present how powerful high-resolution imaging methods can be used to obtain information about the role of individual proteins in nucleocytoplasmic transport and the functional organization of the nuclear pore complex. The fact that mutations in genes encoding human pore complex proteins cause tissue-selective diseases strongly suggests that transport processes are not invariant from one cell to another and that high-resolution analyses, such as those being carried out in yeast, should be used to examine different higher eukaryotic cell types.

Physical connections between the nucleus and cytoplasm

The role of nuclear pore complexes in mediating exchange between the subcellular compartments separated by the nuclear envelope has been studied for several decades. A more recent focus of attention in cell biology is the physical connection between the inside of the nucleus and the cytoskeleton. These connections are mediated primarily by the LINC (linker of nucleoskeleton and cytoskeleton) complex that spans the inner and outer nuclear membranes, interacting with the lamina inside the nucleus and cytoskeletal components in the cytoplasm [22]. Key components of the LINC complex are nesprins (also known as synes), which are transmembrane proteins encoded by at least four genes in mammals, giving rise to various isoforms arising by alternative RNA splicing. In this issue, Morris and Randles [23] review how various nesprin isoforms can be located either in the inner nuclear membrane, outer nuclear membrane or perhaps both. Given their diversity in structure as well as variable localization in the membrane domains of the nuclear envelope and other cellular membranes, nesprin protein family members probably have multiple and complicated functions in tissue differentiation and disease. Indeed, homozygous mutations in SYNE-1 encoding nesprin-1 isoforms can cause either a pure cerebellar ataxia or a syndrome with joint contractures and myopathy [24,25].

Post-translational protein processing

Prelamin A undergoes a series of post-translational modifications and processing steps to yield mature lamin A, which is incorporated into the lamina [16]. This process generates an intermediate with a carboxymethylated and farnesylated C-terminal cysteine residue. This intermediate is cleaved by the endoprotease ZMPSTE24 15 amino acids away from the farnesylated cysteine residue. The de novo LMNA mutations that cause Hutchinson–Gilford progeria syndrome, a rare accelerated aging disorder, generate a cryptic RNA splice donor site, which leads to deletion of 50 amino acids, including the ZMPSTE24 site. As a result, a truncated permanently farnesylated prelamin A called progerin is expressed in patient cells. Genetically modified mice that express progerin develop phenotypic features of progeria and treatment with a farnesyltransferase inhibitor, which blocks protein farnesylation, leads to partial improvement of the abnormal phenotypes [26]. This result suggests that accumulation of an aberrantly farnesylated protein plays an important role in the pathogenesis of progeria. However, it cannot be the entire story, as expression of a non-farnesylated progerin variant also causes less severe, but significant, progeroid phenotypes in mice [27].

In this issue, Smallwood and Shackleton [28] review data showing that aberrant prelamin farnesylation may not be the only pathogenic factor in the pathogenesis of Hutchinson–Gilford progeria syndrome and the implications this has for the design of human clinical trials, some of which are underway. Mehta et al. [29] discuss progerin-induced nucleolar abnormalities and data that farnesyltransferase inhibitors completely reverse them in cells expressing this abnormally prenylated prelamin A variant. Loss of ZMPSTE24 function leading to accumulation of the permanently farnesylated wild-type prelamin A intermediate also causes progeria syndromes. Intriguingly, several HIV protease inhibitors block the activity of this enzyme. Administration of these drugs to patients with HIV infection often leads to development of partial lipodystrophy, which is a feature of many progerias and can also result from LMNA mutations that do not lead to expression of abnormally farnesylated prelamin A, but to amino acid substitutions in mature A-type lamins. Goulbourne and Vaux [30] explore this interesting association and speculate as to whether ZMPSTE24 inhibition by protease inhibitors is a pathogenic mechanism in this acquired form of partial lipodystrophy. Although many questions remain, a picture is emerging in which abnormal post-translational processing of prelamin A underlies some, but not all, cellular defects in progerias and possibly other diseases caused by LMNA mutation.

The nuclear envelope in medicine beyond rare diseases

Each of the laminopathies is a rare or orphan disease arising from inherited or spontaneous mutations. However, emerging data suggest that alterations in the nuclear lamina could occur in more common diseases, particularly cancer. This may not be surprising, given that abnormal nuclear architecture visible using light microscopy is a feature of cancer cells that has been recognized by pathologists for about a century. However, only a small number of studies in recent years have systematically examined nuclear envelope protein expression in cancer. In this issue, Foster et al. [31] assess the use of lamins as cancer biomarkers to diagnose tumours and predict survival. Although expression of A-type lamins appears to be a marker of more differentiated tumours, it has been shown to be either a predictor of good or poor survival depending upon the tumour type. Hence, no different from in the rare monogenic diseases, the functions of lamins and the nuclear envelope in cancer appear to be complex. Perhaps this is a good reason to give scientists more time for research to present at another exciting British Nuclear Envelope Disease and Chromatin Organization meeting.

Nuclear Envelope Disease and Chromatin Organization 2009: Independent Meeting held at College of St Hild and St Bede, University of Durham, Durham, U.K., 22–23 April 2009. Organized and Edited by Chris Hutchison (Durham, U.K.).

Abbreviations

     
  • LINC

    linker of nucleoskeleton and cytoskeleton

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