Mini-reviewGenetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy
Introduction
Proteins of the inner nuclear membrane (INM) are receiving significant attention given the fundamental roles they play in the maintenance of the nuclear envelope (NE) architecture. The INM receives and integrates multiple signals, which must be sorted and coordinated [1]. These aspects are important for all the housekeeping cellular activities and are fundamental during cell division, a process involving nuclear disassembly and its subsequent assembly. Furthermore, it appears that the INM embedded proteins, with the capacity to bind and/or modify chromatin, may be critical in determining the characteristics of differentiated cells. Many INM proteins have been described, among them, emerin, MAN1, Nurim, Dpy19L1 to L4, SUN1 and SUN2, AKAP 149, lamin B receptor (LBR) and lamina-associated polypeptide 1 and 2 (LAP1, LAP2) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Several tumors exhibit abnormal nuclear structures which are likely to involve INM proteins [13]. These morphological alterations appear to be involved in carcinogenesis and have assisted in tumor diagnosis. Many other diseases involving the lamins and associated INM proteins have been intensively studied; these are collectively referred to as laminopathies or nuclear envelopathies [14], [15]. Emerin provided the first link between an INM protein and a human disorder. Emerin is associated with a rare human genetic disease, the X-linked form of Emery–Dreifuss muscular dystrophy [12], [16]. Other examples are the mutations of the LMNA gene (encodes lamin A and C) which are associated with over a dozen different diseases, including cardiac and muscular dystrophies, lipodystrophies and progeria (accelerated aging) [17]. The heterogenous nature of the resulting human disorders reflects the wide array of cellular functions involving lamins, namely resistance of cells to mechanical stress, contribution to structural nuclear integrity, regulation of chromatin structure and gene transcription. Many other proteins interact with lamins, among them the LAP protein family, known to bind both A- and B-type lamins. Moreover, LAP1 binds directly to lamins and indirectly to chromosomes [7]. Therefore LAP1 appears be involved in the positioning of lamins and chromatin in close proximity to the NE, thus contributing to the maintenance of the NE structure [18], [19].
LAP1 is encoded by the TOR1AIP1 gene and is a type-2 integral membrane protein, located in the INM [6], [7], [20]. LAP1 interacts with torsinA and emerin. In fact it appears that the protein complexes associated with the INM are responsible for the tissue specific laminopathies [21] and not the individual proteins.
LAP1 is a pivotal INM associated protein, capable of transducing signals across the INM [21]. It is functionally relevant across many tissues; from muscle, where it associates with emerin, to neurons where it associates with torsinA. As already mentioned LAP1 associates with both lamins and chromosomes. The interaction between LAP1 and lamins appears to be important during interphase, targeting lamins to the nuclear envelope (NE) and contributing to the maintenance of the NE architecture. During prometaphase (NE disassembly), LAP1 seems to redistribute throughout the endoplasmic reticulum (ER), and lose its association to chromosomes and lamins, thus contributing to the NE breakdown [6], [7], [19], [22]. Recently it was shown that, during the cell cycle, LAP1 plays a role in centrosome distancing from the nuclear envelope [23]. This reinforces a role for LAP1 as a key player participating in NE structural maintenance, during progression of the cell cycle. It is particularly noteworthy that LAP1 knockdown resulted in a decrease of mitotic cells and reduced levels of α-tubulin acetylated and lamin B1 [23]. LAP1 is highly phosphorylated during mitosis. In fact, it is plausible that LAP1 is regulated by protein phosphorylation during mitosis, as has been reported for other nuclear proteins [24], [25]. Even so LAP1 function is unclear, and other functions have been attributed to this protein, for example, it has been associated with torsinA ATPase regulation.
Section snippets
LAP1 isoforms
LAP1 was initially identified from rat liver nuclei by a monoclonal antibody generated against lamina-enriched fractions [6]. This antibody recognized three bands from rat liver nuclei, and these were later called LAP1A, LAP1B and LAP1C. Subsequently the same isoforms were described for mouse. In the latter there are at least three RefSeq records corresponding to three different mouse LAP1 transcripts: transcript 1 (NM_001160018) the longest transcript, transcript 2 (NM_144791) is shorter than
LAP1 solubility
Topologically LAP1B resides in the nuclear membrane, where the C-terminus is intramembranous (luminal domain) and the N-terminus is nuclear (nucleoplasmic domain). Early experiments on the rat LAP1 isoforms, showed that LAP1A, LAP1B and LAP1C all located to the INM [6]. Treatment of the nuclear envelope at low salt concentrations, with a nonionic detergent resulted in all LAP1A, all LAP1B and most of LAP1C, remaining associated with the lamina containing the insoluble fraction. However, if the
LAP1 and its complexes
LAP1 binds to more than 30 proteins, however for the purpose of this review focus will be placed on LAP1 binding to torsinA, emerin (Fig. 2) and PP1.
TorsinA is one of the proteins with which LAP1 interacts [32]. The latter is a central protein in DYT1 dystonia, a disease characterized by sustained muscle contractions leading to twisting and repetitive movements or abnormal postures. This phenotype arises as a result of an in frame mutation in the TOR1A gene (encodes torsinA), which removes a
LAP1 and post-translational regulation mechanisms
Reversible protein phosphorylation is the most common type of post-translational modification and a major regulatory cellular event. It is associated with many neuropathological disorders and has been intensely studied [47], [48]. Protein phosphorylation is an important regulatory mechanism for the assembly/disassembly of lamins and the components of the INM. LAP1 is phosphorylated at many sites [24], [25], [49], [50], [51], [52], [53]. Human LAP1B was originally shown to be phosphorylated on
LAP1 mutations
Recently a TOR1AIP1 mutation was reported, affecting three members of a Turkish family with an autosomal recessive limb-girdle muscular dystrophy with joint contractures. The nucleotide deletion is predicted to cause a frameshift and a premature stop codon in the first exon [38] of the TOR1AIP1 gene (Fig. 3). It is predicted that this c.186delG mutation, truncates the 584 amino acid LAP1B protein to an apparently non-functional protein that is only 83 amino acids long [38]. Consequently, LAP1B
Closing remarks
The characteristics of the above mentioned mutations might present a novel putative target, which falls within the recent therapeutic strategies for INM related diseases.
A current approach is to look for stop codon read-through and exon-skipping molecules. The overall approach is to develop gene product modifiers that act on RNA and correct the mutations, as is presently being pursued for the dystrophin gene [60]. Stop codon read-through agents were originally based on gentamicin and related
Acknowledgments
This work was financed by JPND/0006/2011—BIOMARKAPD and supported by PEst-OE/SAU/UI0482/2014; the Fundação para a Ciência e Tecnologia of the Ministério da Educação e Ciência; the COMPETE program, QREN and the European Union (Fundo Europeu de Desenvolvimento Regional).
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