Post-Translational Modification of Lamins: Mechanisms and Functions

Abstract

Lamins are the ancient type V intermediate filament proteins contributing to diverse biological functions, such as the maintenance of nuclear morphology, stabilization of chromatin architecture, regulation of cell cycle progression, regulation of spatial-temporal gene expressions, and transduction of mechano-signaling. Deregulation of lamins is associated with abnormal nuclear morphology and chromatin disorganization, leading to a variety of diseases such as laminopathy and premature aging, and might also play a role in cancer. Accumulating evidence indicates that lamins are functionally regulated by post-translational modifications (PTMs) including farnesylation, phosphorylation, acetylation, SUMOylation, methylation, ubiquitination, and O-GlcNAcylation that affect protein stabilization and the association with chromatin or associated proteins. The mechanisms by which these PTMs are modified and the relevant functionality become increasingly appreciated as understanding of these changes provides new insights into the molecular mechanisms underlying the laminopathies concerned and novel strategies for the management. In this review, we discussed a range of lamin PTMs and their roles in both physiological and pathological processes, as well as potential therapeutic strategies by targeting lamin PTMs.

Keywords: genome regulation; laminopathy; lamins; nucleus; post-translational modification.

FIGURE 1

Structure of the nuclear periphery and lamins. (A) Schematic representation of the nuclear envelope structure. The nuclear lamina lies beneath the inner nuclear membrane and interacts with nuclear proteins and chromatin at lamina-associated domains (LADs). Several nuclear lamina proteins, including lamin A/C, B1, B2, lamin B receptor (LBR), and emerin, are associated with LAD positioning. (B) Schematic structure of lamins. The lamins consist of three domains including an N-terminal head domain, a central coiled-coil rod domain, and a globular C-terminal tail domain with the NLS and Ig-fold. Lamins assemble into higher order filaments through rod domain interactions. Lamin dimers form head-to-tail polymers and then assemble into filaments in an antiparallel manner. (C) Immunofluorescence images of mouse collecting duct cells stained for lamin A/C (red) and lamin B1 (green) and DNA (blue).

FIGURE 2

Post-translational procession of prelamin A, B1, and B2. (A) Post-translational procession of prelamin A to lamin A. Prelamin A undergoes four post-translational chemical reactions before the mature lamin A is formed. Step I, the farnesyltransferase mediates farnesylation of the CAAX motif of prelamin A. Step II, the last tripeptide is clipped off by ZMPSTE24 or RCE1. Step III, ICMT methylates the exposed farnesylated cysteine residue. Step IV, removal of the last 15 amino acid residues by ZMPSTE24, including the C-terminal farnesylcysteine methyl ester. (B) Lamin C does not undergo these processing steps as it does not contain the CAAX motif. The mature lamins B1 and B2 remain permanently farnesylated at their C-termini.

FIGURE 3

Post-translational modifications of lamins and their multifunctional roles. (A) Lamins undergo various PTMs in different domains. (B) Landscape of post-translational modifications and functions. PTMs of lamins are involved in mitosis, viral infection and immune response, nuclear shape and lamin localization, lamin interaction, gene transcription, and DNA damage repair, as well as lamin degradation (modified from Murray-Nerger et al., 2021).

FIGURE 4

Targeting PTMs of defective lamin A to improve Hutchinson–Gilford progeria syndrome (HGPS). Farnesyltransferase inhibitors (FTI) show promising therapeutic effects due to the reduction of progerin accumulation. The orally active FTI lonafarnib (Zokinvy™) has been approved by the FDA to reduce the risk of mortality in HGPS and for the treatment of processing-deficient progeroid laminopathies in patients ≥12 months of age with a body surface area of ≥0.39 m². Isoprenylcysteine carboxyl methyltransferase (ICMT), phosphorylation, SUMOylation, and ubiquitination of farnesylated prelamin A might also be potential targets for treatment.