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Cold Spring Harbor Perspectives in... Feb 2022Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin regulators, signaling molecules, splicing factors, and even chromatin itself... (Review)
Review
Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin regulators, signaling molecules, splicing factors, and even chromatin itself to form a nuclear subcompartment, the nuclear lamina, that is involved in a variety of cellular processes such as the governance of nuclear integrity, nuclear positioning, mitosis, DNA repair, DNA replication, splicing, signaling, mechanotransduction and -sensation, transcriptional regulation, and genome organization. Lamins are the primary scaffold for this nuclear subcompartment, but interactions with lamin-associated peptides in the inner nuclear membrane are self-reinforcing and mutually required. Lamins also interact, directly and indirectly, with peripheral heterochromatin domains called lamina-associated domains (LADs) and help to regulate dynamic 3D genome organization and expression of developmentally regulated genes.
Topics: Cell Nucleus; Chromatin; Lamins; Mechanotransduction, Cellular; Nuclear Envelope; Nuclear Lamina
PubMed: 34400553
DOI: 10.1101/cshperspect.a040113 -
Nature Nov 2015Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with...
Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagy; Autophagy-Related Protein 8 Family; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Senescence; Chromatin; Cytoplasm; Fibroblasts; HEK293 Cells; Humans; Lamin Type B; Lysosomes; Mice; Microfilament Proteins; Microtubule-Associated Proteins; Nuclear Lamina; Oncogene Protein p21(ras); Protein Binding; Proteolysis
PubMed: 26524528
DOI: 10.1038/nature15548 -
Cell Reports Jun 2023The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using...
The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.
Topics: Animals; Mice; Endogenous Retroviruses; Nuclear Lamina; Aging; Cellular Senescence; Neurons; Primates
PubMed: 37261950
DOI: 10.1016/j.celrep.2023.112593 -
Comprehensive Physiology Sep 2016The nucleus is separated from the cytosol by the nuclear envelope, which is a double lipid bilayer composed of the outer nuclear membrane and the inner nuclear membrane.... (Review)
Review
The nucleus is separated from the cytosol by the nuclear envelope, which is a double lipid bilayer composed of the outer nuclear membrane and the inner nuclear membrane. The intermediate filament proteins lamin A, lamin B, and lamin C form a network underlying the inner nuclear membrane. This proteinaceous network provides the nucleus with its strength, rigidity, and elasticity. Positioned within the inner nuclear membrane are more than 150 inner nuclear membrane proteins, many of which interact directly with lamins and require lamins for their inner nuclear membrane localization. Inner nuclear membrane proteins and the nuclear lamins define the nuclear lamina. These inner nuclear membrane proteins have tissue-specific expression and diverse functions including regulating cytoskeletal organization, nuclear architecture, cell cycle dynamics, and genomic organization. Loss or mutations in lamins and inner nuclear membrane proteins cause a wide spectrum of diseases. Here, I will review the functions of the well-studied nuclear lamina proteins and the diseases associated with loss or mutations in these proteins. © 2016 American Physiological Society. Compr Physiol 6:1655-1674, 2016.
Topics: Animals; Humans; Mutation; Nuclear Envelope; Nuclear Matrix; Nuclear Matrix-Associated Proteins
PubMed: 27783855
DOI: 10.1002/cphy.c150039 -
Science (New York, N.Y.) Aug 2013Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue...
Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.
Topics: Adipogenesis; Animals; Cell Differentiation; Collagen; Elasticity; Extracellular Matrix; Gene Expression Regulation, Developmental; Humans; Lamin Type A; Mesenchymal Stem Cells; Mice; Models, Biological; Nuclear Lamina; Osteogenesis; Protein Conformation; Proteome; Stress, Mechanical; Transcription, Genetic; Tretinoin; Vitamin A
PubMed: 23990565
DOI: 10.1126/science.1240104 -
Current Opinion in Cell Biology Jun 2016Many signaling pathways converge on the nucleus to regulate crucial nuclear events such as transcription, DNA replication and cell cycle progression. Although the vast... (Review)
Review
Many signaling pathways converge on the nucleus to regulate crucial nuclear events such as transcription, DNA replication and cell cycle progression. Although the vast majority of research in this area has focused on signals generated in response to hormones or other soluble factors, the nucleus also responds to mechanical forces. During the past decade or so, much has been learned about how mechanical force can affect transcription, as well as the growth and differentiation of cells. Much has also been learned about how force is transmitted via the cytoskeleton to the nucleus and then across the nuclear envelope to the nuclear lamina and chromatin. In this brief review, we focus on some of the key proteins that transmit mechanical signals across the nuclear envelope.
Topics: Animals; Cell Differentiation; Cell Nucleus; Chromatin; Cytoskeleton; Humans; Mechanotransduction, Cellular; Membrane Proteins; Microtubules; Nuclear Envelope; Nuclear Lamina; Nuclear Proteins; Signal Transduction
PubMed: 27018929
DOI: 10.1016/j.ceb.2016.03.006 -
Nucleus (Austin, Tex.) May 2016The nuclear lamina (NL) is a structural component of the nuclear envelope and makes extensive contacts with integral nuclear membrane proteins and chromatin. These... (Review)
Review
The nuclear lamina (NL) is a structural component of the nuclear envelope and makes extensive contacts with integral nuclear membrane proteins and chromatin. These interactions are critical for many cellular processes, such as nuclear positioning, perception of mechanical stimuli from the cell surface, nuclear stability, 3-dimensional organization of chromatin and regulation of chromatin-binding proteins, including transcription factors. The NL is present in all nucleated metazoan cells but its composition and interactome differ between tissues. Most likely, this contributes to the broad spectrum of disease manifestations in humans with mutations in NL-related genes, ranging from muscle dystrophies to neurological disorders, lipodystrophies and progeria syndromes. We review here exciting novel insight into NL function at the cellular level, in particular in chromatin organization and mechanosensation. We also present recent observations on the relation between the NL and metabolism and the special relevance of the NL in muscle tissues. Finally, we discuss new therapeutic approaches to treat NL-related diseases.
Topics: Animals; Cell Movement; Chromatin; Disease; Health; Humans; Nuclear Lamina
PubMed: 27158763
DOI: 10.1080/19491034.2016.1183848 -
Biomedicines Jul 2020Cellular health is reliant on proteostasis-the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance.... (Review)
Review
Cellular health is reliant on proteostasis-the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope-the nuclear lamina-coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.
PubMed: 32630170
DOI: 10.3390/biomedicines8070188 -
Nucleus (Austin, Tex.) Jan 2018The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments... (Review)
Review
The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies). Those disorders in which adipose tissue is affected are called laminopathic lipodystrophies and include type 2 familial partial lipodystrophy and certain premature aging syndromes. This work summarizes the main clinical features of these syndromes, their associated comorbidities and the clues for the differential diagnosis with other lipodystrophic disorders.
Topics: Adipose Tissue; Animals; Cell Nucleus; Humans; Lipodystrophy; Nuclear Lamina
PubMed: 29557732
DOI: 10.1080/19491034.2018.1454167 -
Frontiers in Oncology 2018Aneuploidy, loss or gain of whole chromosomes, is a prominent feature of carcinomas, and is generally considered to play an important role in the initiation and... (Review)
Review
Aneuploidy, loss or gain of whole chromosomes, is a prominent feature of carcinomas, and is generally considered to play an important role in the initiation and progression of cancer. In high-grade serous ovarian cancer, the only common gene aberration is the p53 point mutation, though extensive genomic perturbation is common due to severe aneuploidy, which presents as a deviant karyotype. Several mechanisms for the development of aneuploidy in cancer cells have been recognized, including chromosomal non-disjunction during mitosis, centrosome amplification, and more recently, nuclear envelope rupture at interphase. Many cancer types including ovarian cancer have lost or reduced expression of Lamin A/C, a structural component of the lamina matrix that underlies the nuclear envelope in differentiated cells. Several recent studies suggest that a nuclear lamina defect caused by the loss or reduction of Lamin A/C leads to failure in cytokinesis and formation of tetraploid cells, transient nuclear envelope rupture, and formation of nuclear protrusions and micronuclei during the cell cycle gap phase. Thus, loss and reduction of Lamin A/C underlies the two common features of cancer-aberrations in nuclear morphology and aneuploidy. We discuss here and emphasize the newly recognized mechanism of chromosomal instability due to the rupture of a defective nuclear lamina, which may account for the rapid genomic changes in carcinogenesis.
PubMed: 30524960
DOI: 10.3389/fonc.2018.00529