Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
* Author for correspondence (e-mail: klwilson{at}jhmi.edu)
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Summary |
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Key words: Laminopathy, Emerin, Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome, Nuclear envelope
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Introduction |
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Like other intermediate filament proteins, lamins consist of an N-terminal head domain, a central coiled-coil (rod) domain responsible for dimerization, and a large globular C-terminal tail. The tail includes an immunoglobulin (Ig)-fold domain, the backbone organization of which is unique to lamins, formed by residues 430-545 (Dhe-Paganon et al., 2002; Krimm et al., 2002
). All lamins except lamin C and lamin C2 also contain a CAAX (Cys-aliphatic-aliphatic-any residue) motif at the C-terminus, which is farnesylated on Cys in vivo prior to proteolytic removal of the AAX sequence. Prelamin A is then carboxymethylated and re-cleaved to remove the modified Cys plus 14 additional residues (647-661), yielding mature lamin A (Fig. 1) (Moir et al., 1995
). A site-specific protease named Zmpste24 is proposed to perform both cleavage events (Pendas et al., 2002
). Lamin A is (so far) the only known substrate for Zmpste24 in mammals. Consistent with lamin A being a major substrate is the observation that loss of Zmpste24 causes muscular dystrophy and bone degeneration phenotypes in mice (Bergo et al., 2002
; Pendas et al., 2002
; see below) and mandibuloacral dysplasia in humans (Agarwal et al., 2003
), disorders associated with compromised A-type lamin function.
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Laminopathies |
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The first genetic model for laminopathy was the LMNA-knockout mouse; these mice appear normal at birth but develop severe muscular dystrophy and die within eight weeks (Sullivan et al., 1999). In the first reported human LMNA-null case, a baby possessing a homozygous nonsense mutation in LMNA, with no detectable A-type lamin proteins, died after premature birth, exhibiting severe joint contractures, muscular dystrophy, fibrosis and absence of muscle fibers in the diaphragm (Muchir et al., 2003
). This premature birth and death cannot be attributed exclusively to loss of A-type lamins, because of parental consanguinity and the consequent potential for homozygous defects in other genes. Nonetheless, the resemblance to laminopathy suggests that A-type lamins, although not essential for cell viability, are essential for human life.
Mice have been constructed to express only the L530P-mutated forms of lamins A and C, which causes EDMD in humans (Mounkes et al., 2003). A side-effect of the targeting strategy was that the `knocked-in' L530P allele also changed the mRNA splicing pattern to yield two predicted protein products: mature A-type lamins that lack exon 9, and a C-terminally-truncated lamin A that has 19 extra (intronencoded) internal residues (see supplementary data in Mounkes et al., 2003
). Neither mutation is expected to disrupt C-terminal processing of lamins, but this possibility has not been ruled out. These mice have `progeria-like' pathologies of bone and skin, and die prematurely (Mounkes et al., 2003
). Loss of human Zmpste24 gene activity causes severe mandibuloacral dysplasia with progeroid appearance and general lipodystrophy (Agarwal et al., 2003
), which is altogether less severe than HGPS. Thus, large deletions in the lamin A/C tail (i.e. loss of 50 residues in HGPS, or loss of exon 9 residues in L530P-knock-in mice) might correlate with progeria, and must certainly disrupt lamin organization and interactions. The effects of `progeric' mutations on the assembly and partner-binding activities of A-type lamins will be important to test.
Many plausible disease mechanisms have been proposed. Some models emphasize possible disruption of the mechanical properties of lamin filaments, which control the shape, stiffness and structural integrity of nuclei. Other models view lamins as sites (`scaffolds') for the assembly of other proteins that regulate transcription, cell fate or apoptosis (Burke and Stewart, 2002; Goldman et al., 2002
). Both models are probably correct. We have taken a fresh look at the published binding partners for A-type lamins (Table 1, Fig. 1). Some bind A-type lamins in two-hybrid assays and in vitro, but their in vivo significance remains untested. In other cases, the interactions have also been studied in vivo. Many partners were familiar to us, but others were not. They form four loose groups: architectural partners, chromatin partners, gene-regulatory partners and signaling partners. Clearly, some partners fit multiple categories. What emerges, however, is that a rich variety of protein complexes and biochemical pathways could depend on lamins in vivo.
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Architectural partners |
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The best-studied architectural partner for A-type lamins in the nuclear interior is LAP2, which has separate binding sites for BAF, A-type lamins and chromatin (Dechat et al., 1998
; Dechat et al., 2000
; Vlcek et al., 1999
). LAP2
binds tightly to A-type lamins during interphase (Dechat et al., 2000
), but has dynamic architectural roles during nuclear envelope assembly (Vlcek et al., 2002
). It is proposed to tether A-type lamins to intranuclear sites and to cooperate with lamins in organizing chromatin (Foisner, 2003
). LAP2
(and other LEM-domain proteins) also binds transcriptional regulators (see below), establishing a theme in which `architectural' partners for lamins also influence gene regulation, directly or indirectly.
We do not yet know whether B-type lamins are direct architectural partners for A-type lamins in vivo. A- and B-type lamins have distinct assembly pathways in vivo (Moir et al., 2000), which could mean they form distinct networks. However, B-type lamins might `set the stage' for the assembly of A-type lamins. A-type lamins are known to be architectural partners for each other, since lamin C depends on lamin A for its localization and assembly in the nucleus (Vaughan et al., 2001
).
Actin, actin-related proteins and numerous actin-binding proteins (including a nuclear-specific isoform of myosin I) are present in the nucleus, where their functions are now slowly emerging (Pederson and Aebi, 2002). There is currently no evidence for long actin filaments (F-actin) in the nucleus. However, actin can also form a multitude of special dimers, short protofilaments and tubular, flat or branched oligomers that would suit the chromatin-dominated nuclear space (Pederson and Aebi, 2002
). Interestingly, nuclear actin polymers adopt a unique conformation that is recognized by specific antibodies (Milankov and De Boni, 1993
). Actin binds directly to two regions in the lamin A/C tail: residues 461-536 (in the Ig-fold domain) (M.S.Z. and K.L.W., unpublished) and residues 563-646 (Sasseville and Langelier, 1998
). A-type lamin filaments might thus bind to actin polymers in the nucleus. The possibility that actin polymers are architectural partners for lamin filaments deserves serious attention.
Nesprin 1, a 131 kDa nuclear membrane protein, binds directly to A-type lamins and emerin (Mislow et al., 2002a
; Mislow et al., 2002b
). All nesprin-family proteins (also known as Syne, Myne and NUANCE) have multiple spectrin repeat (SR) domains, and many also have an actin-binding domain (Zhang et al., 2002
; Zhang et al., 2001
; Starr and Han, 2003
). Human nesprins are encoded by two genes, which yield multiple protein isoforms through alternative mRNA splicing and use of internal transcription initiation sites. These isoforms range in mass from huge (
1 MDa for nesprin 1) to modest (e.g. 131 kDa for nesprin 1
) (Mislow et al., 2002a
; Zhang et al., 2002
; Zhang et al., 2001
). Nesprins are anchored to specific membranes, such as the Golgi complex or the outer or inner membrane of the nuclear envelope (Gough et al., 2003
; Mislow et al., 2002b
; Zhang et al., 2001
). Nesprin 1
was proposed to anchor lamin A and emerin at the inner nuclear membrane. However, this model was overthrown by the finding that nesprin 1
and emerin both mislocalize to the endoplasmic reticulum (ER) in human fibroblasts that lack A-type lamins (Muchir et al., 2003
). Transient expression of either lamin A or lamin C is sufficient to relocalize both membrane proteins to the nuclear envelope. These results suggest an architectural hierarchy based on the integrity of A-type lamins.
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Chromatin partners |
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DNA is wound around core histone octamers to form nucleosomes, the fundamental unit of chromatin structure. The human lamin A/C tail binds to mixtures of core histones with an apparent affinity of 300 nM (Taniura et al., 1995), which is similar to its affinity for naked DNA. Since histones and DNA are abundant in the nucleus, given such an affinity A-type lamins are probably always close to chromatin. This would allow lamins to serve as scaffolds for multiprotein complexes associated with chromatin.
BAF is essential for cell viability in C. elegans (Zheng et al., 2000) and Drosophila (Furukawa et al., 2003
). It binds to lamin A with 1 µM affinity in vitro (Holaska et al., 2003
) and also binds to LEM-domain proteins (Furukawa, 1999
; Lee et al., 2001
; Shumaker et al., 2001
; Liu et al., 2003
). However, BAF also qualifies as a `chromatin' partner for lamins because it binds nonspecifically to double-stranded DNA (Zheng et al., 2000
; Shumaker et al., 2001
) and co-localizes with chromatin in certain cell types (e.g. Drosophila embryos) (Furukawa et al., 2003
). Live-cell studies using GFP-fused BAF show direct binding to emerin at the nuclear envelope but also show that GFP-BAF is highly mobile during interphase (Shimi et al., 2004
). In Drosophila embryos, loss of BAF causes chromatin and nuclear envelope defects (Furukawa et al., 2003
). Additional mitotic defects seen in these embryos (e.g. lack of cyclin expression) might reflect a role for BAF in gene expression (see below). Nonetheless, excess BAF present during nuclear assembly can profoundly alter chromatin structure in Xenopus egg extracts (Segura-Totten et al., 2002
), confirming its importance as an architectural partner but not revealing the mechanism. We can only speculate that BAF serves as a chromatin partner for lamin A by rapidly interlinking chromatin, LEM-domain proteins and lamins.
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Gene-regulatory partners |
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SREBP1a and SREBP1c are additional lamin-binding proteins. Encoded by alternatively spliced mRNAs, they are both basic helix-loop-helix leucine zipper transcription factors that, when activated, are released from the ER by proteolytic cleavage and move into the nucleus. Once in the nucleus, they activate genes required for cholesterol biosynthesis and lipogenesis (reviewed by Horton, 2002) and promote adipocyte differentiation (Kim and Spiegelman, 1996
). SREBP proteins bind to the Ig-fold domain of the lamin A/C tail, as do many other partners (Fig. 1). Interestingly, lipodystrophy-causing mutations in A-type lamins reduce SREBP binding by 25-40% (Lloyd et al., 2002
). It will be important to determine which other partners (in addition to SREBP and DNA) are affected by lipodystrophy-causing mutations.
MOK2 is a DNA-binding transcriptional repressor that interacts with lamins A and C. It represses genes activated by cone-rod homeobox protein (Crx) transcription factors by competing with them for binding sites (Dreuillet et al., 2002). MOK2 also binds to RNA in vitro, and might thus influence RNA processing (Arranz et al., 1997
). Like Rb, MOK2 binds to the coil 2 region of A-type lamins (Dreuillet et al., 2002
) (Fig. 1). It therefore seems that A-type lamins have binding site(s) for transcriptional repressors not only in their tail domain, but also in the rod domain. Optimal access to rod domain sites might require a specific oligomeric (dimer, tetramer or octamer) or assembly (filamentous) state.
Another gene-regulatory partner is BAF (see above). BAF binds directly to several different homeodomain transcription activators, including Crx, and represses Crx-dependent gene expression in retinal cells (Wang et al., 2002) (reviewed by Segura-Totten and Wilson, 2004
). Thus, BAF and MOK2 both repress CRX-activated genes, but by different mechanisms (Fig. 2). It is curious that two out of four identified lamin-binding repressors influence Crx-regulated genes, but this might simply reflect the low number of proteins studied so far.
The BAF-binding partner emerin is proposed to be a fifth gene-regulatory partner for A-type lamins. Other LEM-domain proteins (e.g. LAP2ß and MAN1) that bind lamin B inhibit gene expression in vivo (Liu et al., 2003; Nili et al., 2001
; Osada et al., 2003
). Emerin has not yet been tested for such activity in vivo. However, it does form a complex with lamin A and the transcriptional repressor GCL in vitro (Holaska et al., 2003
). Emerin is very special among known binding partners for lamin A/C, because loss of emerin causes the same disease EDMD as many dominant mutations in A-type lamins (Bione et al., 1994
). Perhaps in future other laminopathies will be analogously `paired' to loss of a specific lamin-binding protein(s). Meanwhile the wide expression of emerin in human tissues, and functional overlap between emerin and other LEM-domain proteins make it difficult to pinpoint which function(s) of emerin are critical to the EDMD disease mechanism (Bengtsson and Wilson, 2004
). Further molecular and in vivo dissection of emerin functions is needed to clarify its role in lamin A/C complexes, which might combine roles in nuclear architecture (Fig. 2) and gene regulation.
Various gene regulators thus bind A-type lamins and/or emerin, and this supports the idea that dysregulation of gene expression is an important contributing factor in laminopathies. Furthermore, studies with LEM-domain proteins (emerin, LAP2 and LAP2ß) and transcriptional regulators (GCL, BAF and Rb) also provide the best current evidence that lamins scaffold multiprotein complexes (Holaska et al., 2003
; Markiewicz et al., 2002
; Nili et al., 2001
). Interestingly, the gene regulators known to bind A-type lamins are all repressors. Gene silencing is certainly key to cell differentiation, but it is premature to assume that all gene regulators act repressively when complexed with A-type lamins.
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Signaling partners |
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12(S)-lipoxygenase [12(S)-LOX] also binds to the lamin A/C tail, perhaps overlapping the binding site for PKC (Tang et al., 2000
) (Fig. 1). Interestingly, 12(S)-LOX is part of a lipid-signaling pathway that converts arachidonic acid to 12(S)-HETE, which activates PKC
in prostate tumor cells (Liu et al., 1994
). The 12(S)-LOX protein is detected in both the cytoplasm and nucleus in western blots of cell fractions (Tang et al., 2000
). We speculate that PKC
might translocate to the nucleus and co-dock with 12(S)-LOX on lamin A/C filaments (Fig. 2). Alternatively, nuclear-localized PKC
might be activated in a 12(S)-LOX-dependent manner. The knowledge that PKC
and 12(S)-LOX are both direct partners for lamin A can be used to test the hypothesis that lamin scaffolds are important for PKC
-mediated signal transduction.
The third signaling partner, E1B 19K, is an adenovirus early protein (Cuconati and White, 2002). E1B 19K binds directly to lamin A in two-hybrid assays, and cofractionates with lamins in vivo. In adenovirus-infected cells, E1B 19K, which shares a low level of sequence similarity with Bcl-2, localizes to the ER and nuclear membranes, and blocks apoptosis in a lamin-dependent manner (Rao et al., 1997
). E1B 19K also interacts with (and potentially inactivates) a death-promoting repressor named Btf (Kasof et al., 1999
), which binds to emerin in vitro (Haraguchi et al., 2004
). Does E1B 19K bind lamin A in order to co-assemble with Btf on emerin-lamin complexes, or might it displace Btf? By considering each strand in this web of interactions, we may be able to understand how each partner `uses' lamin A.
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Perspectives |
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References |
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