Abstract
The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.
Highlights
Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain
Envelopathies are rare diseases stemming from mutations in nuclear envelope encoding genes including lamin, proteins from the inner nuclear membrane, such as emerin or SUN proteins, outer nuclear membranes, such as nesprins and proteins involved in the regulation of NE proteins such as ZMPSTE24 [59]
Nearly 500 mutations have been identified in Lamin A (LMNA), which cause a plethora of diseases such as Emery–Dreifuss Muscular Dystrophy (EDMD), dilated cardiomyopathy (DCM), Hutchinson–Gilford Progeria Syndrome (HGPS), Lipodystrophy syndrome, and peripheral neuropathy
Summary
The main role of the nuclear envelope (NE) is to compartmentalize and protect the unfolded genomic DNA from the cytoplasm in eukaryote cells. It is composed of a lipid bilayer reinforced in its inner side with a sheet-like structure of proteins called the nuclear lamina. The outer nuclear membrane (ONM) shares a common border with the endoplasmic reticulum (ER). The nuclear envelope has many nuclear pores that facilitate the transport of molecules between the cytosol and the nucleus (Figure 1A). The NE is a dynamic organelle that expends, disrupts and reconstitutes during mitosis. It constantly remodels to adapt to nuclear growth
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