Lamin post-translational modifications: emerging toggles of nuclear organization and function

Lamins are ancient intermediate filaments that mediate critical nuclear processes by maintaining nuclear shape, stabilizing chromatin, regulating transcription, and contributing to cell cycle progression. The two classes of lamins form overlapping networks at the nuclear periphery but have distinct regulatory roles. Technological advances revealed an expansive range of post-translational modifications that decorate lamins, including phosphorylation, acetylation, ubiquitination, SUMOylation, methylation, and O-GlnAcylation. While phosphorylation is a known regulator of mitotic laminar disruption, diverse post-translational modifications are being established as toggles of lamin arrangement, interactions, and functions. The emerging field of lamin post-translational modification has wide-ranging implications in laminopathies, cancer progression, and viral pathogen infections. Nuclear lamins are ancient type V intermediate filaments with diverse functions that include maintaining nuclear shape, mechanosignaling, tethering and stabilizing chromatin, regulating gene expression, and contributing to cell cycle progression. Despite these numerous roles, an outstanding question has been how lamins are regulated. Accumulating work indicates that a range of lamin post-translational modifications (PTMs) control their functions both in homeostatic cells and in disease states such as progeria, muscular dystrophy, and viral infection. Here, we review the current knowledge of the diverse types of PTMs that regulate lamins in a site-specific manner. We highlight methods that can be used to characterize lamin PTMs whose functions are currently unknown and provide a perspective on the future of the lamin PTM field. Nuclear lamins are ancient type V intermediate filaments with diverse functions that include maintaining nuclear shape, mechanosignaling, tethering and stabilizing chromatin, regulating gene expression, and contributing to cell cycle progression. Despite these numerous roles, an outstanding question has been how lamins are regulated. Accumulating work indicates that a range of lamin post-translational modifications (PTMs) control their functions both in homeostatic cells and in disease states such as progeria, muscular dystrophy, and viral infection. Here, we review the current knowledge of the diverse types of PTMs that regulate lamins in a site-specific manner. We highlight methods that can be used to characterize lamin PTMs whose functions are currently unknown and provide a perspective on the future of the lamin PTM field. the addition of an acetyl group to an amino acid side chain; neutralizes the positive charge of the amino acid. alpha-helical domain of lamins that mediates lamin–lamin interactions and assembly into higher order filaments. the addition of an isoprenoid lipid to a cysteine side chain at a CaaX motif. N terminal domain of lamins. a method of double-strand break DNA repair that depends on extensive homology and is predominately active in S/G2 cell cycle phases. C terminal domain of lamins that mediates interactions with non-lamin proteins. phase of the cell cycle (including G1, S, and G2) during which a cell grows, replicates its genome, and prepares to divide. a type V intermediate filament that localizes at the inner nuclear membrane, maintains nuclear stability, and regulates nuclear processes. heterochromatic DNA regions associated with the lamina at the nuclear periphery. genetic diseases caused by mutation in a lamin-encoding gene; examples are Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome. degradation by the lysosome, a membrane-bound organelle that contains hydrolytic enzymes that can degrade proteins. the addition of a methyl group to an amino acid side chain. membrane-enclosed compartments containing fragmented genetic material or whole chromosomes. the stage of the cell cycle in which one cell divides into two daughter cells with the same number of chromosomes as the parent cell. a double-strand break DNA repair pathway that functions throughout the cell cycle, depends on the direct ligation of broken DNA ends, and does not require extensive homology. a type of virus that replicates its genome inside the host cell nucleus; examples are herpesviruses and adenoviruses. the addition of the sugar ß-O-linked N-acetylglucosamine to an amino acid side chain. the addition of a phosphate group to an amino acid side chain. the enzymatic or non-enzymatic addition of a range of chemical functional groups or small proteins to amino acid side chains. the form of lamin A that is expressed prior to additional post-translational processing. a mutant form of lamin A in which 50 amino acids are deleted, causing Zmpste24 cleavage site removal and inducing permanent farnesylation; its expression causes progeria. degradation by the proteasome, a multi-subunit protein complex that degrades proteins by breaking their peptide bonds. the addition of the small ubiquitin-like modifier (SUMO) protein to an amino acid side chain. the addition of the small protein ubiquitin to an amino acid side chain; can target a protein for proteasomal degradation. a coat of virally encoded proteins inside which the viral genome is packaged.