Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease

Abstract

The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.

Keywords: Envelopathies; Lipodystrophy; Myopathy; Neuropathy; Nonalcoholic Fatty Liver Disease; Nucleoskeleton; Progeria.

Figure 1.

Structure of the nuclear envelope including nuclear pore complex, LINC complex, and the nuclear lamina. Schematic of the nuclear envelope structure including outer and inner nuclear membranes, the lamina, integral membrane proteins, nuclear pore complex, LINC complexes, components of the cytoplasmic cytoskeleton, and chromatin-lamina contacts. The outer nuclear membrane is shown in continuity with the membrane of the endoplasmic reticulum (ER). A portion of LMNA (red) is shown as a soluble nucleoplasmic protein, some of which is bound to LAP2α.

Figure 2.

Affected pathways in laminopathies and potential avenues for therapeutic intervention. Alterations in multiple pathways contribute to the pathogenesis of laminopathies. Strategies tested in preclinical or clinical studies are indicated with solid arrows. Strategies to alter Wnt signaling to β-catenin or growth hormone signaling via Jak and Stat proteins, which are altered in mouse models of laminopathies but have not been tested in animal models or clinical trials, are indicated with dashed arrows. Agents developed to reduce or block activity of progerin, FTIs^,,,, antisense oligonucleotides, and small molecules that inhibit progerin interaction with LMNA have been tested.