International Journal of Molecular Sciences Review Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation Benoit R. Gauthier 1,2,* and Valentine Comaills 1,* 1 Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain 2 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain * Correspondence: [email protected] (B.R.G.); [email protected] (V.C.) 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 Citation: Gauthier, B.R.; Comaills, V. of therapeutics. Nuclear Envelope Integrity in Health and Disease: Consequences on Keywords: nuclear envelope; nuclear envelope disruption; inflammation; cGAS/STING; chromoso- Genome Instability and Inflammation. mal instability; envelopathy; cancer; lipodystrophy; neuropathy Int. J. Mol. Sci. 2021, 22, 7281. https://doi.org/10.3390/ijms22147281 Academic Editor: Ivan Y. Iourov 1. Nuclear Envelope Biology The main role of the nuclear envelope (NE) is to compartmentalize and protect the Received: 23 June 2021 unfolded genomic DNA from the cytoplasm in eukaryote cells. It is composed of a lipid Accepted: 4 July 2021 Published: 6 July 2021 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 endoplas- mic reticulum (ER). The nuclear envelope has also many nuclear pores that facilitate the Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in transport of molecules between the cytosol and the nucleus (Figure1A). The NE is a dy- published maps and institutional affil- namic organelle that expends, disrupts and reconstitutes during mitosis. In the interphase, iations. it constantly remodels to adapt to nuclear growth. 1.1. Nuclear Lamina The lamina conveys strength, flexibility, and rigidity as a function of its variable composition and ratio among the various lamins [1,2]. In addition to providing mechanical Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. support and being an anchorage platform, the nuclear lamina regulates important cellular This article is an open access article events such as DNA replication [3] and cell division [4]. The lamina is primordial for distributed under the terms and gene regulation [5,6] through the repression of genes in the Lamin-Associated Domain conditions of the Creative Commons (LAD, Figure C), DNA repair [7], organization of the nucleolus [8], as well as chromosomal Attribution (CC BY) license (https:// positioning [9]. The Lamina contributes to the organization of the genome into its different creativecommons.org/licenses/by/ compartments: (i) the heterochromatin, characterized by repressed DNA that is tethered 4.0/). into the LAD, (ii) the euchromatin, the active compartment with a loose chromatin structure Int. J. Mol. Sci. 2021, 22, 7281. https://doi.org/10.3390/ijms22147281 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7281 2 of 26 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 27 that is active for transcription, and (iii) the nucleolus, the site of ribosome production and assembly (Figure1A). FigureFigure 1. Nuclear 1. Nuclear envelope envelope composition composition and and organization. organization. ( (AA)).. The nucleusnucleus is is surrounded surrounded by by the the nuclear nuclear envelope envelope (NE). (NE). The OuterThe Outer Nuclear Nuclear Membrane Membrane (ONM) (ONM) is iscontinuous continuous with with the endoplasmicendoplasmic reticulum. reticulum. The The nuclear nuclear pore pore complex complex (NPC) (NPC) regulatesregulates the export the export and and import import between between thethe nucleusnucleus and and the the cytoplasm. cytoplasm. The genomeThe genome is organized is organized in different in compartments:different compart- ments:euchromatin, euchromatin, heterochromatin, heterochromatin and nucleolus., and nucleolus. (B). Structure (B). Structure of lamin layersof lamin in the layers Inner in Nuclear the Inner Membrane Nuclear (INM). Membrane (C). The (INM). (C). TheNE NE is composed is composed of a lipid of a bilayerlipid bi anchoredlayer anc byhored several by proteins several formingproteins the forming lamin-associated the lamin protein,-associated the LINC protein, complex, the LINC complexand, byand the by lamins. the lamins. The NE The proteins NE protein regulates regulate gene organization gene organization with the Lamin-Associated with the Lamin Domain-Associated (LAD). Domain (LAD). 1.1. NuclearThe lamina Lamina also possesses mechano-responsivity in order to adapt to the cell’s environ- ment. Lamin levels are dynamic, regulated by cell differentiation, and depend on the tissue The lamina conveys strength, flexibility, and rigidity as a function of its variable com- stiffness [2,10]. Lamins are interconnected to the cytoskeleton by intermediate proteins positionsuch as and the ratio Linker among of the Nucleoskeletonthe various lamins and Cytoskeleton[1,2]. In addition (LINC) to complex providing composed mechanical supportby SUN1/2 and being and Nesprinsan anchorage proteins platform, (Figure 1theC), nuclear which allow lamina sensing regulates and rapidimportant cellular cellular eventsresponse such via as theDNA complex replication post-translational [3] and cell controldivision of [4] its. proteins The lamina [2,11 ].is The primordial NE can also for gene regulationadapt in response[5,6] through to stiffness the repression [2] or to function. of gene Fors in example, the Lamin migrasive-Associated and invasive Domain cells (LAD, Figureneed C), to acquireDNA repair nuclear [7] elasticity, organization and can of decrease the nuc nuclearleolus envelope[8], as well proteins as chromosomal in order to po- sitioningcompress [9] through. The Lamina narrow contributes space [1,10,12 to]. the organization of the genome into its different compartments:The nuclear (i) the lamina heterochromatin, is composed of laminscharacterized and nuclear by repressed lamin-associated DNA membranethat is tethered proteins (Figure1B,C). Lamins are type V intermediate filaments fibrous proteins that into the LAD, (ii) the euchromatin, the active compartment with a loose chromatin struc- are divided into two major categories, the A and B type. The gene LMNA can be spliced turein that two is predominant active for transcription isoforms, the, longer and (iii) version the nucleolus, encoding thethe protein site of Laminribosome A and production the andshorter assembly isoform (Figure generating 1A). the Lamin C protein. The type B lamins are expressed by two differentThe lamina genes: alsoLMNB1 possessesand LMNB2 mechano, encoding-responsivity Lamin in B1 order and B2, to respectively.adapt to the Whilecell’s envi- ronmeLaminnt. ALamin is expressed levels are in differentiateddynamic, regulated cells, type by Bcell lamins differentiation are ubiquitously, and expresseddepend on the tissuein all stiffness cells. Similar [2,10]. toLamins other are intermediate interconnected filament to proteins,the cytoskeleton lamins self-assemble by intermediate into pro- teinscomplex such as structures. the Linker Lamins of the are Nucleoske highly dynamicleton and and C regulatedytoskeleton proteins (LINC) that complex assemble com- posedand by disassemble SUN1/2 and pending Nesprins stimuli proteins [13]. They (Figure are organized 1C), which into allow distinct sensing networks and at rapid the cel- nuclear periphery [14] (Figure1B). Lamin B1 forms an outer concentric ring, and its lular response via the complex post-translational control of its proteins [2,11]. The NE can also adapt in response to stiffness [2] or to function. For example, migrasive and invasive cells need to acquire nuclear elasticity and can decrease nuclear envelope proteins in order to compress through narrow space [1,10,12]. The nuclear lamina is composed of lamins and nuclear lamin-associated membrane proteins (Figure 1B,C). Lamins are type V intermediate filaments fibrous proteins that are divided into two major categories, the A and B type. The gene LMNA can be spliced in two predominant isoforms, the longer version encoding the protein Lamin A and the Int.