The Nuclear Envelope Lumen is Continuous With the Er Lumen
What is the nuclear envelope? By separating the genome from the cytoplasm, the nuclear envelope defines the hallmark of eukaryotic cells, the cell nucleus. The envelope is made up of inner and outer nuclear membranes, which enclose a lumen, the perinuclear space, which is continuous with the endoplasmic reticulum (ER) lumen. The inner and outer nuclear membranes are connected at the sites of nuclear pore complexes, large, aqueous protein channels that mediate all traffic through the nuclear envelope. Underneath the inner nuclear membrane of multicellular organisms lies the nuclear lamina, a peripheral meshwork of intermediate filament proteins called lamins and their associated proteins (Figure 1).
What is the function of the nuclear envelope? It is a barrier separating nuclear processes such as transcription from cytoplasmic processes such as translation. The selective transport of macromolecules between the two compartments of a eukaryotic cell via nuclear pore complexes makes it possible for gene expression to be regulated, for example at the levels of pre-mRNA splicing and mRNA degradation, not seen in simpler prokaryotic cells. It is increasingly evident, however, that the nuclear envelope is not simply a passive barrier: it also has a critical role in the organization of chromatin, gene expression, nuclear anchorage to the cytoskeleton and cell division.
So how do molecules get in and out of the nucleus? The nuclear pore complexes, made up of about thirty different proteins termed nucleoporins, serve as selective gates in the nuclear envelope. The hydrophobic interior of the channel excludes macromolecules depending on their size and hydrophilicity. While small (<40 kDa) or hydrophobic molecules can diffuse passively through the nuclear pore complex, larger hydrophilic proteins rely on nuclear import/export signals, recognized by nuclear transport receptors. These receptors mediate passage through the hydrophobic interior of the nuclear pore complex channel by weak interactions with phenylalanine-glycine repeats of nucleoporins. Translocation through the pore is not energy dependent, but GTP hydrolysis by the small GTPase Ran provides the energy for transport directionality and recycling of the receptors.
Are the nuclear envelope membranes different from the ER? The outer nuclear membrane is directly continuous with the rough ER, has a similar protein composition and is also decorated by ribosomes. However, a small set of specialized proteins, involved in anchorage of the nucleus to the cytoskeleton, are specifically enriched in the outer nuclear membrane. Although it is continuous with the outer nuclear membrane at each nuclear pore complex, the inner nuclear membrane has a very different protein composition. How is this specialized membrane domain created and maintained? Inner nuclear membrane transmembrane proteins with small cytoplasmic and luminal domains appear to rely on a diffusion/retention mechanism: they reach the inner nuclear membrane by passive diffusion from the ER through the membrane connection at the pore, and are retained by binding to nuclear interaction partners like the nuclear lamina, chromatin or both. For other inner nuclear membrane proteins, an active import pathway, analogous to that of soluble nuclear proteins, has recently been discovered. Such active transport of transmembrane proteins is likely to be required for several inner nuclear membrane proteins with large cytoplasmic domains and relies on the presence of nuclear import signals.
What is the nuclear lamina? A dense network of protein filaments, termed the nuclear lamina, underlies the inner nuclear membrane. This peripheral structure is composed of two types of lamins, which are members of the intermediate filament family, as well as interacting inner nuclear membrane and soluble proteins. The B-type lamins are ubiquitously expressed and in their mature form carry a carboxy-terminal farnesylation which mediates association with the inner nuclear membrane. A/C-type lamins are made only in differentiated cells; they arise from splice variants of a single gene and their farnesyl modification is removed by proteolytic cleavage during maturation. Once assembled, the lamina as well as the nuclear pore complexes anchored in it are very stable throughout interphase. The lamina is thought to have mainly a structural role in stabilizing the shape of the nucleus.
What is the connection between the nuclear envelope and chromatin? The role of the nuclear envelope in global as well as local organization of the genome becomes more and more apparent. Several inner nuclear membrane proteins share a conserved LEM (named after LAP2, Emerin and MAN1) domain, which mediates interactions with the DNA-binding protein BAF (barrier-to-autointegration factor) and, in the case of the LEM-like domains in LAP2, directly with DNA. MAN1 has also been shown to interact with certain transcription factors and could thus be directly involved in regulation of gene expression. Constitutive heterochromatin is often concentrated close to the nuclear envelope, and heterochromatic regions such as the telomeres of yeast chromosomes associate specifically with the nuclear envelope. But, also in yeast, the association of reporter genes with nuclear pores has been shown to promote their transcriptional activity, by a mechanism involving Nup50 and Ran. Thus, the nuclear envelop likely accommodates silenced heterochromatin domains in close proximity to highly active genes, and we are just beginning to understand the molecular mechanisms of this level of gene expression regulation.
How is the nucleus connected to the rest of the cell? The nucleus is anchored in the cell by proteins that link the lamina and chromosomes in the nucleoplasm with the cytoskeleton. On the cytoplasmic side, this anchorage is mediated by Nesprins and related proteins containing a KASH (Klarsicht, ANC-1 and Syne homology) domain. These proteins interact with elements of the cytoskeleton via their cytoplasmic domains, span the outer nuclear membrane and interact with the SUN (Sad1 and UNC-84 homology) domain of inner nuclear membrane proteins in the perinuclear space via their KASH domain. SUN domain proteins in turn interact with the nuclear interior and the lamina, mechanically linking the cytoplasm and nucleus by direct protein–protein interactions.
What happens to the nuclear envelope when the cell divides? Chromosome segregation during cell division in higher eukaryotes is driven by a microtubule spindle formed in the cytoplasm. To allow the interaction of microtubules and chromosomes, the nuclear envelope breaks down in prophase, leading to an 'open' mitosis. Nuclear envelope breakdown occurs by stepwise disassembly of nuclear pore complexes, inner nuclear membrane proteins and, finally, lamins, and is thought to be driven mostly by the phosphorylation of these proteins by mitotic kinases. In somatic cells, nuclear envelope breakdown is additionally facilitated by mitotic microtubules, which pull on the nuclear envelope creating invaginations which eventually cause rupturing of the stretched nuclear lamina. Nuclear membranes are absorbed by the ER, where nuclear membrane proteins disperse by diffusion. Interestingly, some nuclear envelope proteins appear to have additional functions in mitosis; for example, a subset of nucleoporins becomes part of the kinetochore complex that mediates microtubule–chromosome attachment and these nucleoporins are required for faithful chromosome segregation.
And how does the nuclear envelope reform? In species with an open mitosis, reformation of the nuclear envelope starts during anaphase and lasts into G1 phase of the cell cycle. Nuclear assembly is regulated both by the reversal of the mitotic phosphorylation of many nuclear envelope proteins and by the local action of Ran on chromosomes. The first proteins of the nuclear envelope known to bind to chromatin in anaphase are a subset of nucleoporins; these are followed by proteins of the inner nuclear membrane, which accumulate in ER membrane domains adjacent to anaphase chromatin, most likely by interacting with their binding partners on chromatin. Closure of these ER-derived membranes around chromatin and incorporation of nuclear pores requires membrane fusion events, the mechanism of which is still largely unknown. The nuclear lamina only reforms after the nuclear envelope has been sealed and functional nuclear pores import lamins into the nucleus.
Are there any diseases related to the nuclear envelope? Nuclear envelope proteins are implicated in many human diseases, though they tend to be very rare. Various nuclear envelope proteins are targets of autoantibodies in autoimmune diseases such as primary biliary cirrhosis. Defects in nucleocytoplasmic transport, altered expression of nuclear transport factors and chromosomal translocations of nucleoporins have all been implicated in certain types of human cancer. Mutations in the nucleoporin ALADIN cause triple A syndrome, a complex disease characterized by a particular combination of severe tissue specific defects. The largest disease group associated with the nuclear envelope are termed laminopathies, because they result from mutations mainly in the lamin A/C gene, but also in lamin interacting proteins like emerin or proteins involved in the biogenesis of mature lamin A. Although these proteins are ubiquitously expressed, the diseases exhibit diverse tissue specific symptoms ranging from myopathies and neuropathies to lipopathies and progeria syndromes (premature aging), depending on the specific mutation in the gene. The molecular mechanisms of these diseases are not yet understood; hypotheses range from failure to resist mechanical stress in muscle to aberrant regulation of gene expression.
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DOI: https://doi.org/10.1016/j.cub.2006.12.035
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