Huntington\'s disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington\'s disease and other polyglutamine diseases.

Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM.

The endosomal sorting complex required for transport (ESCRT) machinery is composed of an articulated architecture of proteins that assemble at multiple cellular sites. The ESCRT machinery is involved in pathways that are pivotal for the physiology of the cell, including vesicle transport, cell division, and membrane repair. The subunits of the ESCRT I complex are mainly responsible for anchoring the machinery to the action site. The ESCRT II subunits function to bridge and recruit the ESCRT III subunits. The latter are responsible for finalizing operations that, independently of the action site, involve the repair and fusion of membrane edges. In this review, we report on the data related to the activity of the ESCRT machinery at two sites: the nuclear membrane and the midbody and the bridge linking cells in the final stages of cytokinesis. In these contexts, the machinery plays a significant role for the protection of genome integrity by contributing to the control of the abscission checkpoint and to nuclear envelope reorganization and correlated resilience. Consistently, several studies show how the dysfunction of the ESCRT machinery causes genome damage and is a codriver of pathologies, such as laminopathies and cancer.

BACKGROUND: The nuclear envelope (NE), which is composed of the outer and inner nuclear membranes, the nuclear pore complex and the nuclear lamina, regulates a plethora of cellular processes, including those that restrict cancer development (genomic stability, cell cycle regulation, and cell migration). Thus, impaired NE is functionally related to tumorigenesis, and monitoring of NE alterations is used to diagnose cancer. However, the chronology of NE changes occurring during cancer evolution and the connection between them remained to be precisely defined, due to the lack of appropriate cell models.
METHODS: The expression and subcellular localization of NE proteins (lamins A/C and B1 and the inner nuclear membrane proteins emerin and β-dystroglycan [β-DG]) during prostate cancer progression were analyzed, using confocal microscopy and western blot assays, and a prostate cancer cell system comprising RWPE-1 epithelial prostate cells and several prostate cancer cell lines with different invasiveness.
RESULTS: Deformed nuclei and the mislocalization and low expression of lamin A/C, lamin B1, and emerin became more prominent as the invasiveness of the prostate cancer lines increased. Suppression of lamin A/C expression was an early event during prostate cancer evolution, while a more extensive deregulation of NE proteins, including β-DG, occurred in metastatic prostate cells.
CONCLUSIONS: The RWPE-1 cell line-based system was found to be suitable for the correlation of NE impairment with prostate cancer invasiveness and determination of the chronology of NE alterations during prostate carcinogenesis. Further study of this cell system would help to identify biomarkers for prostate cancer prognosis and diagnosis.

The autophagy-lysosomal pathway enables the controlled degradation of cellular contents. Nucleophagy is the selective autophagic recycling of nuclear components upon delivery to the lysosome. Although methods to monitor and quantify autophagy as well as selective types of autophagy have been developed and implemented in cells and in vivo, methods monitoring nucleophagy remain scarce. Here, we describe a procedure to monitor the autophagic engagement of an endogenous nuclear envelope component, i.e., ANC-1, the nematode homologue of the mammalian Nesprins in vivo, utilizing super-resolution microscopy.

The four main types of biomolecules are nucleic acids, proteins, carbohydrates and lipids. The knowledge about their respective interactions is as important as the individual understanding of each of them. However, while, for example, the interaction of proteins with the other three groups is extensively studied, that of nucleic acids and lipids is, in comparison, very poorly explored. An iconic paradigm of physical (and likely functional) proximity between DNA and lipids is the case of the genomic DNA in eukaryotes: enclosed within the nucleus by two concentric lipid bilayers, the wealth of implications of this interaction, for example in genome stability, remains underassessed. Nuclear lipid-related phenotypes have been observed for 50 years, yet in most cases kept as mere anecdotical descriptions. In this review, we will bring together the evidence connecting lipids with both the nuclear envelope and the nucleoplasm, and will make critical analyses of these descriptions. Our exploration establishes a scenario in which lipids irrefutably play a role in nuclear homeostasis.

Mitosis exhibits astonishing evolutionary plasticity, with dividing eukaryotic cells differing in the organization of the mitotic spindle and the extent of nuclear envelope breakdown. A new study suggests that a multinucleated lifestyle may favor the evolution of closed nuclear division.

To coordinate cellular physiology, cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites. Lipid droplets (LDs) and nuclear membrane (NM) contact sites are particularly vital communication hubs, playing key roles in the exchange of signaling molecules, lipids, and metabolites. However, there is still a lack of understanding of the specific morphology of the contact sites. Here, we combine advanced three-dimensional (3D) imaging with a high-brightness fluorescent probe specifically targeting LDs to map the structural landscape of LD-NM contact sites. The probe exhibits exceptional photophysical properties, making it highly suitable for visualizing the changes occurring in LDs during the apoptosis process. In addition, we utilize the advantages of the probe to accurately monitor the overexpression of abnormal LDs in cirrhosis by 3D imaging for the first time. The outcomes of this investigation highlight that the probe has potential as a robust imaging tool to investigate intricate biological functions of LDs and their implications in related diseases.

Recent studies in yeast reveal an intricate interplay between nuclear envelope (NE) architecture and lipid metabolism, and between lipid signaling and both epigenome and genome integrity. In this review, we highlight the reciprocal connection between lipids and histone modifications, which enable metabolic reprogramming in response to nutrients. The endoplasmic reticulum (ER)-NE regulates the compartmentalization and temporal availability of epigenetic metabolites and its lipid composition also impacts nuclear processes, such as transcriptional silencing and the DNA damage response (DDR). We also discuss recent work providing mechanistic insight into lipid droplet (LD) formation and sterols in the nucleus, and the collective data showing Opi1 as a central factor in both membrane sensing and transcriptional regulation of lipid-chromatin interrelated processes.

Precise temporal and sequential control of gene expression during development and in response to environmental stimuli requires tight regulation of the physical contact between gene regulatory elements and promoters. Current models describing how the genome folds in 3D space to establish these interactions often ignore the role of the most stable structural nuclear feature - the nuclear envelope. While contributions of 3D folding within/between topologically associated domains (TADs) have been extensively described, mechanical contributions from the nuclear envelope can impact enhancer-promoter interactions both directly and indirectly through influencing intra/inter-TAD interactions. Importantly, these nuclear envelope contributions clearly link this mechanism to development and, when defective, to human disease. Here, we discuss evidence for nuclear envelope regulation of tissue-specific enhancer-promoter pairings, potential mechanisms for this regulation, exciting recent findings that other regulatory elements such as microRNAs and long noncoding RNAs are under nuclear envelope regulation, the possible involvement of condensates, and how disruption of this regulation can lead to disease.