Delbarre, E. et al. The truncated prelamin A in Hutchinson-Gilford progeria syndrome alters segregation of A-type and B-type lamin homopolymers. Hum. Mol. Genet. 15, 1113-1122

Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Université Paris 6 and 7, 2 Place Jussieu Tour 43, 75251 Paris Cedex 05, France.
Human Molecular Genetics (Impact Factor: 6.39). 05/2006; 15(7):1113-22. DOI: 10.1093/hmg/ddl026
Source: PubMed


Hutchinson-Gilford progeria syndrome (HGPS) is a dominant autosomal premature aging syndrome caused by the expression of a truncated prelamin A designated progerin (Pgn). A-type and B-type lamins are intermediate filament proteins that polymerize to form the nuclear lamina network apposed to the inner nuclear membrane of vertebrate somatic cells. It is not known if in vivo both type of lamins assemble independently or co-assemble. The blebbing and disorganization of the nuclear envelope and adjacent heterochromatin in cells from patients with HGPS is a hallmark of the disease, and the ex vivo reversal of this phenotype is considered important for the development of therapeutic strategies. Here, we investigated the alterations in the lamina structure that may underlie the disorganization caused in nuclei by Pgn expression. We studied the polymerization of enhanced green fluorescent protein- and red fluorescent protein-tagged wild-type and mutated lamins in the nuclear envelope of living cells by measuring fluorescence resonance energy transfer (FRET) that occurs between the two fluorophores when tagged lamins interact. Using time domain fluorescence lifetime imaging microscopy that allows a quantitative analysis of FRET signals, we show that wild-type lamins A and B1 polymerize in distinct homopolymers that further interact in the lamina. In contrast, expressed Pgn co-assembles with lamin B1 and lamin A to form a mixed heteropolymer in which A-type and B-type lamin segregation is lost. We propose that such structural lamina alterations may be part of the primary mechanisms leading to HGPS, possibly by impairing functions specific for each lamin type such as nuclear membrane biogenesis, signal transduction, nuclear compartmentalization and gene regulation.

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Available from: Marc Tramier, Feb 12, 2014
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    • "It has been observed in vivo that A-and B-type lamins preferentially form homopolymers and that heterotypic interaction of lamins occurs between juxtaposed A-and B-type lamin homopolymers [39]. Furthermore , it was reported in amphibian oocytes that different lamin proteins form distinctive individual filaments with characteristic organization . "
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    ABSTRACT: We recently characterized a nuclear import pathway for β-dystroglycan; however, its nuclear role remains unknown. In this study, we demonstrate for the first time, the interaction of β-dystroglycan with distinct proteins from different nuclear compartments, including the nuclear envelope (NE) (emerin and lamins A/C and B1), splicing speckles (SC35), Cajal bodies (p80-coilin), and nucleoli (Nopp140). Electron microscopy analysis revealed that β-dystroglycan localized in the inner nuclear membrane, nucleoplasm, and nucleoli. Interestingly, downregulation of β-dystroglycan resulted in both mislocalization and decreased expression of emerin and lamin B1, but not lamin A/C, as well in disorganization of nucleoli, Cajal bodies, and splicing speckles with the concomitant decrease in the levels of Nopp140, and p80-coilin, but not SC35. Quantitative reverse transcription PCR and cycloheximide-mediated protein arrest assays revealed that β-dystroglycan deficiency did not change mRNA expression of NE proteins emerin and lamin B1 bud did alter their stability, accelerating protein turnover. Furthermore, knockdown of β-dystroglycan disrupted NE-mediated processes including nuclear morphology and centrosome-nucleus linkage, which provides evidence that β-dystroglycan association with NE proteins is biologically relevant. Unexpectedly, β-dystroglycan-depleted cells exhibited multiple centrosomes, a characteristic of cancerous cells. Overall, these findings imply that β-dystroglycan is a nuclear scaffolding protein involved in nuclear organization and NE structure and function, and that might be a contributor to the biogenesis of nuclear envelopathies.
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    • "In addition, the LA/C meshwork in the NE of LMNB D/D MEFs exhibits a dramatic increase in mesh size (Vergnes et al., 2004). Additional evidence for interaction between these two lamin meshworks comes from studies using fluorescence resonance energy transfer (FRET) in combination with time domain fluorescence lifetime imaging and high resolution confocal immunofluorescence (Delbarre et al., 2006; Moir et al., 2000; Shimi et al., 2008). A small but significant fraction of both A-and B-type lamins are also present throughout the nuclear interior during interphase. "

    Full-text · Article · Nov 2011 · Advances in enzyme regulation
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    • "However, B type lamins undergo partial proteolysis by the enzyme Rce1 and remain permanently farnesylated. Farnesylation of B type lamins has been implicated in their anchorage to the nuclear membrane, but might also mediate protein–protein interactions [Maske et al., 2003; Delbarre et al., 2006]. EMERIN Emerin is the first nuclear envelope protein associated with laminopathies [Bione et al., 1994]. "
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    ABSTRACT: Laminopathies are genetic diseases due to mutations or altered post-translational processing of nuclear envelope/lamina proteins. The majority of laminopathies are caused by mutations in the LMNA gene, encoding lamin A/C, but manifest as diverse pathologies including muscular dystrophy, lipodystrophy, neuropathy, and progeroid syndromes. Lamin-binding proteins implicated in laminopathies include lamin B2, nuclear envelope proteins such as emerin, MAN1, LBR, and nesprins, the nuclear matrix protein matrin 3, the lamina-associated polypeptide, LAP2alpha and the transcriptional regulator FHL1. Thus, the altered functionality of a nuclear proteins network appears to be involved in the onset of laminopathic diseases. The functional interplay among different proteins involved in this network implies signaling partners. The signaling effectors may either modify nuclear envelope proteins and their binding properties, or use nuclear envelope/lamina proteins as platforms to regulate signal transduction. In this review, both aspects of lamin-linked signaling are presented and the major pathways so far implicated in laminopathies are summarized.
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