Nuclear membrane
Ever since Robert Brown's discovery of the nucleus in 1833 it has been known that the nucleus is surrounded by a membranous
structure. Today the function of the nuclear membrane, also known as the nuclear envelope, is much better understood. The nuclear membrane is a lipid
bilayer enclosing the nucleus and the membrane physically isolates the nucleus from the rest of the cell, which enables separate molecular processes in
each cellular compartment to occur, without interference. Example images of proteins localized to the nuclear membrane can be seen in Figure 1. Of all human proteins, approximately 276 (1%) have been experimentally shown to
localize to the nuclear membrane (Figure 2). A Gene Ontology (GO)-based functional enrichment analysis of the nuclear membrane proteins shows enriched
terms for biological processes mainly related to molecular transport. About 84% (n=233) of the nuclear membrane proteins localize to other cellular
compartments in addition to the nuclear membrane, whereof 39% (n=92) are other nuclear structures. The most common additional localizations except the
nucleoplasm are the cytosol and vesicles.
The structure of the nuclear membrane
The nuclear membrane consists of two linked lipid layers, where the outermost membrane is anchored to the endoplasmic reticulum
and the innermost membrane acts as an anchoring site of chromatin. The chromatin is attached to the nuclear lamina of the membrane, a fibrillar network
consisting of intermediate filament proteins. Although it is not yet clear how lamin proteins are organized in the cell
(Gruenbaum et al, 2005) they are known to act both as a mechanical support for the nucleus and function to organize chromatin by anchoring it to the
nuclear lamina, both through binding to histones, as well as directly to the DNA. It has been suggested that lamins may also participate in DNA repair,
as well as regulation of DNA replication and transcription
(Dechat et al,. 2008). Lamins are classified as A- or B-type, and exhibit different biochemical and functional properties in terms of isoelectric points
and behavior during mitosis. During the mitotic phase of cell division, B-type lamins will remain associated to membranes, whereas A-type lamins are
solubilized and dispersed
(Gruenbaum et al, 2005; Stuurman et al, 1998). A selection of the lamins localized to the nuclear membrane and other proteins
suitable as marker proteins for the nuclear membrane, can be found in Table 1. A list of highly expressed nuclear membrane proteins, including
lamins, are summarized in Table 2.
Table 1. Selection of proteins suitable as markers for the nuclear membrane.
Gene |
Description |
Substructure |
SUN2
|
Sad1 and UNC84 domain containing 2 |
Nuclear membrane |
TMPO
|
Thymopoietin |
Nuclear membrane |
SUN1
|
Sad1 and UNC84 domain containing 1 |
Nuclear membrane |
LEMD2
|
LEM domain containing 2 |
Nuclear membrane |
LMNB1
|
Lamin B1 |
Nuclear membrane |
TOR1AIP1
|
Torsin 1A interacting protein 1 |
Nuclear membrane |
LBR
|
Lamin B receptor |
Nuclear membrane |
LMNB2
|
Lamin B2 |
Nuclear membrane |
Table 2. Highly expressed single localized nuclear membrane proteins across different cell lines.
Gene |
Description |
Average TPM |
TMPO
|
Thymopoietin |
133 |
LMNB1
|
Lamin B1 |
82 |
LBR
|
Lamin B receptor |
81 |
LMNB2
|
Lamin B2 |
76 |
SUN2
|
Sad1 and UNC84 domain containing 2 |
48 |
NUP153
|
Nucleoporin 153 |
47 |
TPR
|
Translocated promoter region, nuclear basket protein |
45 |
SUN1
|
Sad1 and UNC84 domain containing 1 |
40 |
TOR1AIP1
|
Torsin 1A interacting protein 1 |
40 |
LEMD2
|
LEM domain containing 2 |
39 |
The space between the inner and the outer membrane is called the perinuclear space. Nuclear pore complexes are distributed
throughout the membrane at several places where the inner and outer layer meet, each one consisting of 100-200 proteins that form a characteristic
eightfold ring symmetry
(Paine et al, 1975; Reichelt et al, 1990;
Callan et al, 1950). When imaging an intersection of the cell, the nuclear membrane is visible as a thin circle
along the outer rim of the nucleus, which is consistent between cell lines (Figure 3). The membrane is however not perfectly smooth and the
membranous cavities can appear as small circles or dots inside the nucleus, not to be confused with nuclear bodies.
See the morphology of the nuclear membrane in human induced stem cells in the Allen Cell Explorer. The function of the nuclear membrane
The nuclear membrane serves as a barrier between the nucleus and the cytoplasm, allowing controlled gene regulation and
transcription in the nuclear area
(Callan et al, 1950;
Watson, 1955). The nuclear pores allow for active transport of small molecules, but also larger proteins, between the nucleus
and the cytoplasm
(Paine et al, 1975; Bahr et al, 1954). In that sense, the nuclear membrane creates both a barrier, but also a linkage between the nucleus and the rest
of the cell. The nuclear membrane is a highly dynamic structure and the structural composition is altered throughout the cell cycle. During the G2
phase, the nuclear membrane expands as a result of the chromosome duplication. The membrane is broken down in the prometaphase to enable connection of the centrosome and the spindle apparatus to the sister chromatids during mitosis. The breakdown mechanism involves disassembly of the nuclear pore complexes,
depolymerization of the nuclear lamina, removal of proteins associated to the inner nuclear membrane. Reassembly of the nuclear membrane occures after the
completion of the mitosis
(Terasaki et al, 2001; Dultz et al, 2008;
Salina et al, 2002;
Beaudouin et al, 2002; Gerace et al, 1980;
Ellenberg et al, 1997;
Yang et al, 1997). Mutations in genes encoding
nuclear lamina associated proteins might give rise to several diseases collectively called laminopathies. One example is the protein emerin that
mediates anchoring of the nuclear membrane to the cytoskeleton (Figure 6). Mutations in the EMD gene causes Emery-Dreifuss muscular dystrophy (EDMD),
an X chromosome linked disease characterized by contractures and in many cases also cardiomyopathy
(Bione et al, 1994).
Gene Ontology (GO) analysis of the proteins mainly localized to the nuclear membrane shows functions that are well in line with already known
functions for the structure. The enriched terms for the GO domain Biological Process are mostly related to molecular transport (Figure 4a).
Enrichment analysis of the GO domain Molecular Function, give top hits for terms related to lamins, nuclear pore complexes and nuclear trafficking
(Figure 4b).
Nuclear membrane proteins with multiple locations
Of the nuclear membrane proteins identified in the Cell Atlas, approximately 84% (n=233) also localize to other cell compartments
(Figure 5). Of these, 39% (n=92) are other nuclear structures. The network plot shows that the most common locations shared with the nuclear membrane
are the nucleoplasm, cytosol and vesicles. Given that the nuclear membrane acts as the barrier between the nucleus and the cytoplasm, the proteins
localized to the nuclear membrane and cytosol or vesicles could highlight proteins functioning in nuclear trafficking. The number of proteins
localized to the nuclear membrane and the nucleoplasm are seen more often than expected with the current distribution of multilocalizing proteins,
which could be proteins stabilizing the structure of both the nucleus and the membrane or proteins involved in nuclear export.
Examples of multilocalizing proteins within the nuclear membrane proteome can be seen in Figure 6.
Expression levels of nuclear membrane proteins in tissue
The transcriptome analysis (Figure 7) shows that nuclear membrane proteins are not likely to show any type of tissue
specificity, compared to all genes with protein data in the Cell Atlas.
Relevant links and publications
BAHR GF et al, 1954. The fine structure of the nuclear membrane in the larval salivary gland and midgut of Chironomus. Exp Cell Res.
PubMed: 13173504 Beaudouin J et al, 2002. Nuclear envelope breakdown proceeds by microtubule-induced tearing of the lamina. Cell.
PubMed: 11792323 Bione S et al, 1994. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet.
PubMed: 7894480 DOI: 10.1038/ng1294-323 CALLAN HG et al, 1950. Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscope. Proc R Soc Lond B Biol Sci.
PubMed: 14786306 Dechat T et al, 2008. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev.
PubMed: 18381888 DOI: 10.1101/gad.1652708 Dultz E et al, 2008. Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells. J Cell Biol.
PubMed: 18316408 DOI: 10.1083/jcb.200707026 Ellenberg J et al, 1997. Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis. J Cell Biol.
PubMed: 9298976 Gerace L et al, 1980. The nuclear envelope lamina is reversibly depolymerized during mitosis. Cell.
PubMed: 7357605 Gruenbaum Y et al, 2005. The nuclear lamina comes of age. Nat Rev Mol Cell Biol.
PubMed: 15688064 DOI: 10.1038/nrm1550 Paine PL et al, 1975. Nuclear envelope permeability. Nature.
PubMed: 1117994 Reichelt R et al, 1990. Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components. J Cell Biol.
PubMed: 2324201 Salina D et al, 2002. Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell.
PubMed: 11792324 Stuurman N et al, 1998. Nuclear lamins: their structure, assembly, and interactions. J Struct Biol.
PubMed: 9724605 DOI: 10.1006/jsbi.1998.3987 Terasaki M et al, 2001. A new model for nuclear envelope breakdown. Mol Biol Cell.
PubMed: 11179431 WATSON ML. 1955. The nuclear envelope; its structure and relation to cytoplasmic membranes. J Biophys Biochem Cytol.
PubMed: 13242591 Yang L et al, 1997. Integral membrane proteins of the nuclear envelope are dispersed throughout the endoplasmic reticulum during mitosis. J Cell Biol.
PubMed: 9182656 |