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Nucleus (Austin, Tex.) Dec 2019LINC complexes (Linker of Nucleoskeleton and Cytoskeleton), consisting of inner nuclear membrane SUN (Sad1, UNC-84) proteins and outer nuclear membrane KASH (Klarsicht,... (Review)
Review
LINC complexes (Linker of Nucleoskeleton and Cytoskeleton), consisting of inner nuclear membrane SUN (Sad1, UNC-84) proteins and outer nuclear membrane KASH (Klarsicht, ANC-1, and Syne Homology) proteins, are essential for nuclear positioning, cell migration and chromosome dynamics. To test the in vivo functions of conserved interfaces revealed by crystal structures, Cain et al used a combination of Caenorhabditis elegans genetics, imaging in cultured NIH 3T3 fibroblasts, and Molecular Dynamic simulations, to study SUN-KASH interactions. Conserved aromatic residues at the -7 position of the C-termini of KASH proteins and conserved disulfide bonds in LINC complexes play important roles in force transmission across the nuclear envelope. Other properties of LINC complexes, such as the helices preceding the SUN domain, the longer coiled-coils spanning the perinuclear space and higher-order organization may also function to transmit mechanical forces generated by the cytoskeleton across the nuclear envelope.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Proteins; Mice; NIH 3T3 Cells; Nuclear Envelope; Nuclear Proteins; Receptors, Cytoplasmic and Nuclear
PubMed: 30888237
DOI: 10.1080/19491034.2019.1595313 -
Critical Reviews in Biochemistry and... 2015Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity... (Review)
Review
Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that have led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Disease Models, Animal; Dystonia Musculorum Deformans; HSC70 Heat-Shock Proteins; Humans; Membrane Proteins; Molecular Chaperones; Molecular Sequence Data; Mutation; Protein Transport; Sequence Alignment
PubMed: 26592310
DOI: 10.3109/10409238.2015.1091804 -
Annual Review of Virology Sep 2023Nuclear egress of herpesvirus capsids across the intact nuclear envelope is an exceptional vesicle-mediated nucleocytoplasmic translocation resulting in the delivery of... (Review)
Review
Nuclear egress of herpesvirus capsids across the intact nuclear envelope is an exceptional vesicle-mediated nucleocytoplasmic translocation resulting in the delivery of herpesvirus capsids into the cytosol. Budding of the (nucleo)capsid at and scission from the inner nuclear membrane (INM) is mediated by the viral nuclear egress complex (NEC) resulting in a transiently enveloped virus particle in the perinuclear space followed by fusion of the primary envelope with the outer nuclear membrane (ONM). The dimeric NEC oligomerizes into a honeycomb-shaped coat underlining the INM to induce membrane curvature and scission. Mutational analyses complemented structural data defining functionally important regions. Questions remain, including where and when the NEC is formed and how membrane curvature is mediated, vesicle formation is regulated, and directionality is secured. The composition of the primary enveloped virion and the machinery mediating fusion of the primary envelope with the ONM is still debated. While NEC-mediated budding apparently follows a highly conserved mechanism, species and/or cell type-specific differences complicate understanding of later steps.
Topics: Viral Proteins; Herpesviridae; Nuclear Envelope; Capsid Proteins; Capsid; Cell Nucleus; Virus Release
PubMed: 37040797
DOI: 10.1146/annurev-virology-111821-105518 -
Current Opinion in Cell Biology Feb 2024The nuclear-localized lamins have long been thought to be the only intermediate filaments (IFs) with an impact on the architecture, properties, and functions of the... (Review)
Review
The nuclear-localized lamins have long been thought to be the only intermediate filaments (IFs) with an impact on the architecture, properties, and functions of the nucleus. Recent studies, however, uncovered significant roles for IFs other than lamins (here referred to as "non-lamin IFs") in regulating key properties of the nucleus in various cell types and biological settings. In the cytoplasm, IFs often occur in the perinuclear space where they contribute to local stiffness and impact the shape and/or the integrity of the nucleus, particularly in cells under stress. In addition, selective non-lamin IF proteins can occur inside the nucleus where they partake in fundamental processes including nuclear architecture and chromatin organization, regulation of gene expression, cell cycle progression, and the repair of DNA damage. This text reviews the evidence supporting a role for non-lamin IF proteins in regulating various properties of the nucleus and highlights opportunities for further study.
Topics: Lamins; Intermediate Filament Proteins; Cell Nucleus; Intermediate Filaments; Nuclear Envelope
PubMed: 38113712
DOI: 10.1016/j.ceb.2023.102303 -
Nature Plants Jul 2023The nuclear lamina is a complex network of nuclear lamins and lamin-associated nuclear membrane proteins, which scaffold the nucleus to maintain structural integrity. In...
The nuclear lamina is a complex network of nuclear lamins and lamin-associated nuclear membrane proteins, which scaffold the nucleus to maintain structural integrity. In Arabidopsis thaliana, nuclear matrix constituent proteins (NMCPs) are essential components of the nuclear lamina and are required to maintain the structural integrity of the nucleus and specific perinuclear chromatin anchoring. At the nuclear periphery, suppressed chromatin overlapping with repetitive sequences and inactive protein-coding genes are enriched. At a chromosomal level, plant chromatin organization in interphase nuclei is flexible and responds to various developmental cues and environmental stimuli. On the basis of these observations in Arabidopsis, and given the role of NMCP genes (CRWN1 and CRWN4) in organizing chromatin positioning at the nuclear periphery, one can expect considerable changes in chromatin-nuclear lamina interactions when the global chromatin organization patterns are being altered in plants. Here we report the highly flexible nature of the plant nuclear lamina, which disassembles substantially under various stress conditions. Focusing on heat stress, we reveal that chromatin domains, initially tethered to the nuclear envelope, remain largely associated with CRWN1 and become scattered in the inner nuclear space. By investigating the three-dimensional chromatin contact network, we further reveal that CRWN1 proteins play a structural role in shaping the changes in genome folding under heat stress. Also, CRWN1 acts as a negative transcriptional coregulator to modulate the shift of the plant transcriptome profile in response to heat stress.
Topics: Nuclear Lamina; Cell Nucleus; Chromatin; Nuclear Envelope; Lamins; Arabidopsis
PubMed: 37400513
DOI: 10.1038/s41477-023-01457-2 -
Small GTPases Sep 2018Small GTPases of the Rab protein family control intracellular vesicular trafficking to allow their communication and maintenance. It is a common strategy for... (Review)
Review
Small GTPases of the Rab protein family control intracellular vesicular trafficking to allow their communication and maintenance. It is a common strategy for intracellular bacteria to exploit these pathways to shape their respective niches for survival. The subversion of Rabs for the generation of an intracellular environment favoring the pathogen has been described almost exclusively for intracellular bacteria that reside within bacterial containing vacuoles (BCVs). However, less is known about Rab subversion for bacteria that rupture the BCV to reach the host cytoplasm. Here, we provide recent examples of Rab targeting by both groups of intracellular bacteria with a special focus on Shigella, the causative agent of bacillary dysentery. Shigella recruits Rab11, the hallmark of the perinuclear recycling compartment to in situ formed macropinosomes at the entry foci via the bacterial effector IpgD. This leads to efficient BCV rupture and cytosolic escape. We discuss the concept of diverted recycling through host Rab GTPases that emerges as a novel pathogen strategy.
Topics: Humans; Intracellular Space; Shigella; Vacuoles; rab GTP-Binding Proteins
PubMed: 27763815
DOI: 10.1080/21541248.2016.1240494 -
Science Advances May 2024Mutations in the gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in...
Mutations in the gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, -deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the cardiomyopathy development.
Topics: Animals; Lamin Type A; Mice; Nuclear Envelope; Cardiomyopathies; Myocytes, Cardiac; Autophagy; Stress, Physiological; Disease Models, Animal; Endoplasmic Reticulum Stress; Golgi Apparatus; Mice, Knockout
PubMed: 38718107
DOI: 10.1126/sciadv.adh0798 -
JACC. Basic To Translational Science Aug 2020Excessive autophagy induces a defined form of cell death called autosis, which is characterized by unique morphological features, including ballooning of perinuclear... (Review)
Review
Excessive autophagy induces a defined form of cell death called autosis, which is characterized by unique morphological features, including ballooning of perinuclear space and biochemical features, including sensitivity to cardiac glycosides. Autosis is observed during the late phase of reperfusion after a period of ischemia and contributes to myocardial injury. This review discusses unique features of autosis, the involvement of autosis in myocardial injury, and the molecular mechanism of autosis. Because autosis promotes myocardial injury under some conditions, a better understanding of autosis may lead to development of novel interventions to protect the heart against myocardial stress.
PubMed: 32875173
DOI: 10.1016/j.jacbts.2020.04.014 -
Current Opinion in Cell Biology Jun 2016Torsin ATPases are the only members of the AAA+ ATPase family that localize to the endoplasmic reticulum and contiguous perinuclear space. Accordingly, they are well... (Review)
Review
Torsin ATPases are the only members of the AAA+ ATPase family that localize to the endoplasmic reticulum and contiguous perinuclear space. Accordingly, they are well positioned to perform essential work in these compartments, but their precise functions remain elusive. Recent studies have deciphered an unusual ATPase activation mechanism relying on Torsin-associated transmembrane cofactors, LAP1 or LULL1. These findings profoundly change our molecular view of the Torsin machinery and rationalize several human mutations in TorsinA or LAP1 leading to congenital disorders, symptoms of which have recently been recapitulated in mouse models. Here, we review these recent advances in the Torsin field and discuss the most pressing questions in relation to nuclear envelope dynamics.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Disease Models, Animal; Dystonia; Endoplasmic Reticulum; HSC70 Heat-Shock Proteins; Humans; Molecular Chaperones; Mutation; Nuclear Envelope
PubMed: 26803745
DOI: 10.1016/j.ceb.2016.01.001 -
Viruses Nov 2021Herpesvirus capsids are assembled in the nucleus and undergo a two-step process to cross the nuclear envelope. Capsids bud into the inner nuclear membrane (INM) aided by... (Review)
Review
Herpesvirus capsids are assembled in the nucleus and undergo a two-step process to cross the nuclear envelope. Capsids bud into the inner nuclear membrane (INM) aided by the nuclear egress complex (NEC) proteins UL31/34. At that stage of egress, enveloped virions are found for a short time in the perinuclear space. In the second step of nuclear egress, perinuclear enveloped virions (PEVs) fuse with the outer nuclear membrane (ONM) delivering capsids into the cytoplasm. Once in the cytoplasm, capsids undergo re-envelopment in the Golgi/trans-Golgi apparatus producing mature virions. This second step of nuclear egress is known as de-envelopment and is the focus of this review. Compared with herpesvirus envelopment at the INM, much less is known about de-envelopment. We propose a model in which de-envelopment involves two phases: (i) fusion of the PEV membrane with the ONM and (ii) expansion of the fusion pore leading to release of the viral capsid into the cytoplasm. The first phase of de-envelopment, membrane fusion, involves four herpes simplex virus (HSV) proteins: gB, gH/gL, gK and UL20. gB is the viral fusion protein and appears to act to perturb membranes and promote fusion. gH/gL may also have similar properties and appears to be able to act in de-envelopment without gB. gK and UL20 negatively regulate these fusion proteins. In the second phase of de-envelopment (pore expansion and capsid release), an alpha-herpesvirus protein kinase, US3, acts to phosphorylate NEC proteins, which normally produce membrane curvature during envelopment. Phosphorylation of NEC proteins reverses tight membrane curvature, causing expansion of the membrane fusion pore and promoting release of capsids into the cytoplasm.
Topics: Capsid; Cell Nucleus; Cytoplasm; Herpesviridae; Herpesviridae Infections; Humans; Membrane Fusion; Nuclear Envelope; Phosphorylation; Simplexvirus; Viral Envelope; Viral Fusion Proteins; Virion; trans-Golgi Network
PubMed: 34960625
DOI: 10.3390/v13122356