Lamin proteins and their roles in nuclear structural support, cell morphology and ageing

By Andres Hernandez Maduro

Intracellular metabolic proteins are fundamental to the viability of life, and none are arguably more important than those involved in DNA regulation and maintenance. Nuclear lamin proteins, required for structural support of the nucleus and DNA repair, are just as significant.

Nuclear lamins are a subset of intermediate filament proteins that form a protein meshwork on the nucleoplasmic layer of the nuclear envelope, collectively known as the nuclear lamina. Though these exist in practically all eukaryotes, there are four predominant kinds in mammalian cells – two A-type lamins (A and C) and two B-type lamins (B1 and B2). Generally, A-type lamins scaffolding confer stiffness and viscosity to the nucleus, helping it to maintain its shape and density throughout a cell’s interphase. In comparison, B-type lamins provide elasticity to the envelope, and are particularly useful in mitigating the constant mechanical and osmotic pressure changes in the cell’s environment.1

Lamin networks have further been shown to both inhibit and stimulate gene expression in the nucleus, acting either as ‘peripheral traps’ for transcription factors to bind to (away from chromatin) or as platforms to catalyse transcription-inducing reactions. Interestingly, this provides several applications aside from structural support of the nucleus, including in the regulation of actin polymerisation by emerin proteins2 (more on this later) and even in cell proliferation pathways. In the latter case, previous studies have found that extracellular signal-regulated kinases (ERKs) can displace retinoblastoma proteins (pRb) bound to the nuclear lamina, thereby triggering the cdk-dependent phosphorylation of pRB and the start of cell division.3

Lamins are crucial for the intercommunication between the nucleus and the cytoplasm. This is especially true for mechano-signalling pathways, in which the nucleus alters its form and metabolism in response to the forces asserted on its surroundings.1 Dispersed mainly along the apical side of the nucleus (the side furthest from the plasma membrane), specialised zones on the nuclear envelope known as transmembrane actin-associated nuclear (TAN) complexes use A-type lamins as anchors for cytoplasmic proteins to hold on to. Together, these form connections between the nuclear lamina and cytoskeletal actin filaments through a structure known as a linker of nucleoskeleton and cytoskeleton (LINC) complex. In turn, whenever the encompassing cell is stretched or compressed, the forces are transmitted via actin and TAN/LINC complexes in order to stretch A-type lamin proteins.4 Lamins A and C can thereby stimulate signalling cascades to support the cell by phosphorylating emerin proteins, for example, which causes them to increase ATP-capping and polymerisation of actin filaments. Ultimately, this ends up reinforcing TAN complexes and the cytoskeleton, allowing it to better withstand the mechanical strain.2 Furthermore, some researchers suggest that the deformation of lamins leads to decreased access to the lamina of nuclear kinases. Since nuclear lamins can only form a meshwork together when dephosphorylated (as they must allow the disintegration of the nucleus during mitosis), fewer kinases would mean that more lamins would be able to bind together and form a stronger nuclear lamina, resisting outside forces more easily.5

Clearly, lamin filaments are critical for the nucleus to remain dynamic and responsive to the cell’s environment. Consequently, it should be of little surprise that deleterious mutations in lamin genes have proven to be universally crippling in human babies – if not simply fatal to them. Most associated conditions are caused by over 600 different mutations in the LMNA gene, which encodes lamins A and C (though a few others come from LMNB1 mutations).6 The conditions associated with such mutations are referred to as laminopathies, and they include muscular dystrophy; metabolic diseases, such as familial partial lipodystrophy (FPLD); peripheral neuronal diseases; and even conditions associated with early ageing. Both Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, for instance, are the results of LMNA mutations.6 Many of these conditions are heritable and autosomal dominant, and so there is much interest in developing effective treatments for them.

Several different models have been proposed to explain laminopathies.7 Some suggest that lamin mutations reduce how well nuclei are able to resist mechanical stress, resulting in increased nuclear fragility and cell senescence (particularly in muscle cells that regularly experience increased strain through physical exertion). Others state that mutant lamins stimulate the deregulation of genes and alter the phenotype of specific tissues, and yet others say that they might exhibit toxicity inside certain cells. In all likelihood, each model is more relevant in different conditions, particularly as they all produce similar effects. Each is hypothesised to cause significant damage and susceptibility to mutations in DNA, prompting decreased cell and tissue specialisation around the body.7 Given the variability of laminopathies, however, further research is needed to more accurately predict the effect of specific lamin mutations on human health. With modern advances in synthetic biology, genetic engineering and DNA sequencing, our understanding of nuclear lamins may eventually allow for the development of laminopathic treatments and further insights in the process of ageing.

References:

  1. Osmanagic-Myers S, Dechat T, Foisner R. Lamins at the crossroads of mechanosignaling. Genes Dev. 2015 Feb 1;29(3):225-37. Available from: http://www.genesdev.org/cgi/doi/10.1101/gad.255968.114 
  2. Holaska JM, Kowalski AK, Wilson, KL. Emerin Caps the Pointed End of Actin Filaments: Evidence for an Actin Cortical Network at the Nuclear Inner Membrane. PLoS Biol 2:E231. Available from: https://doi.org/10.1371/journal.pbio.0020231 
  3. Rodríguez J, et al. ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma–lamin A complexes. J Cell Biol 29 November 2010;191(5):967–979. Available from: https://doi.org/10.1083/jcb.201004067
  4. Chambliss A, et al. The LINC-anchored actin cap connects the extracellular milieu to the nucleus for ultrafast mechanotransduction. Sci Rep 2013;3:1087. Available from: https://doi.org/10.1038/srep01087
  5. Buxboim  A, et al. Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin. Curr Biol 2014;24:1909-1917. Available from: https://doi.org/10.1016/j.cub.2014.07.001 
  6. Medalia O, et al. Nuclear Lamins: Thin Filaments with Major Functions. Trends in Cell Biology 2018;28(1):34-45. Available from: https://doi-org.iclibezp1.cc.ic.ac.uk/10.1016/j.tcb.2017.08.004 
  7. Gruenbaum Y, Foisner R. Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annual Review of Biochemistry 2015;84:131-164. Available from: https://doi.org/10.1146/annurev-biochem-060614-034115 

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