LINC complex

The concept of mechanotransduction to the nucleus through a direct force transmission mechanism has fascinated cell biologists for decades. Central to such a mechanism is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which spans the nuclear envelope to couple the cytoplasmic cytoskeleton to the nuclear lamina. In reality, there is not one LINC complex identity, but instead a family of protein configurations of varied composition that exert both shared and unique functions. Regulated expression of LINC complex components, splice variants, and mechanoresponsive protein turnover mechanisms together shape the complement of LINC complex forms present in a given cell type...

BACKGROUND: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM...

Linker of nucleoskeleton and cytoskeleton complexes consist of outer nuclear membrane KASH proteins, interacting in the nuclear envelope lumen with inner nuclear membrane SUN proteins and connecting nucleus and cytoskeleton. The paralogous Arabidopsis KASH proteins SINE1 and SINE2 function during stomatal dynamics induced by light-dark transitions and ABA, which requires F-actin reorganization. SINE2 influences actin depolymerization and SINE1 actin repolymerization. The actin-related protein 2/3 (ARP2/3) complex, an actin nucleator, and the plant actin bundling and stabilizing factor SCAB1 are involved in stomatal aperture control...

Connections between the nucleus and the cytoskeleton are important for positioning and division of the nucleus. In most eukaryotes, the LINC complex (Linker of Nucleoskeleton and Cytoskeleton) spans the outer and inner nuclear membranes and connects the nucleus to the cytoskeleton. In opisthokonts, it is composed of Klarsicht, ANC-1 and Syne Homology (KASH) domain proteins and Sad1 and UNC-84 (SUN) domain proteins. Given that the nucleus is positioned at the posterior pole of Toxoplasma gondii, we speculated that apicomplexan parasites must have a similar mechanism that integrates the nucleus and the cytoskeleton...

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex serves to connect the nuclear envelope and the cytoskeleton, influencing cellular processes such as nuclear arrangement, architecture, and mechanotransduction. The role LINC plays in mechanotransduction pathways in bone progenitor cells has been well studied; however, the mechanisms by which LINC complexes govern in vivo bone formation remain less clear. To bridge this knowledge gap, we established a murine model disrupting LINC using transgenic Prx-Cre mice and floxed Tg(CAG-LacZ/EGFP-KASH2) mice...

Successful nuclear migration through constricted spaces between cells or in the extracellular matrix relies on the ability of the nucleus to deform. Little is known of how this takes place in vivo. We study confined nuclear migration in Caenorhabditis elegans larval P-cells, which is mediated by the LINC complex to pull nuclei towards the minus ends of microtubules. Null mutations of LINC component unc-84 lead to a temperature-dependent phenotype, suggesting a parallel pathway for P-cell nuclear migration. A forward genetic screen for enhancers of unc-84 identified cgef-1 (CDC-42 Guanine Nucleotide Exchange Factor)...

CENP-A chromatin specifies mammalian centromere identity, and its chaperone HJURP replenishes CENP-A when recruited by the Mis18 complex (Mis18C) via M18BP1/KNL2 to CENP-C at kinetochores during interphase. However, the Mis18C recruitment mechanism remains unresolved in species lacking M18BP1, such as fission yeast. Fission yeast centromeres cluster at G2 spindle pole bodies (SPBs) when CENP-ACnp1 is replenished and where Mis18C also localizes. We show that SPBs play an unexpected role in concentrating Mis18C near centromeres through the recruitment of Mis18 by direct binding to the major SPB linker of nucleoskeleton and cytoskeleton (LINC) component Sad1...

Durotaxis is a phenomenon in which cells migrate toward substrates of increasing stiffness. However, how cells assimilate substrate stiffness as a directional cue remains poorly understood. In this study, we experimentally show that mouse embryonic fibroblasts can discriminate between different substrate stiffnesses and develop higher traction forces at regions of the cell adhering to the stiffer pillars. In this way, the cells generate a force imbalance between adhesion sites. It is this traction force imbalance that drives durotaxis by providing directionality for cell migration...

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formation in vivo , however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice...

We have recently identified the aberrant nuclear accumulation of the ESCRT-III protein CHMP7 as an initiating event that leads to a significant injury to the nuclear pore complex (NPC) characterized by the reduction of specific nucleoporins (Nups) from the neuronal NPC in sporadic ALS (sALS) and C9orf72 ALS/FTD induced pluripotent stem cell (iPSC) derived neurons (iPSNs), a phenomenon also observed in postmortem patient tissues. Importantly, this NPC injury is sufficient to contribute to TDP-43 dysfunction and mislocalization, a common pathological hallmark of neurodegenerative diseases...

Nuclear migration through narrow constrictions is important for development, metastasis, and pro-inflammatory responses. Studies performed in tissue culture cells have implicated LINC (linker of nucleoskeleton and cytoskeleton) complexes, microtubule motors, the actin cytoskeleton, and nuclear envelope repair machinery as important mediators of nuclear movements through constricted spaces. However, little is understood about how these mechanisms operate to move nuclei in vivo . In C. elegans larvae, 6 pairs of hypodermal P cells migrate from lateral to ventral positions through a constricted space between the body wall muscles and the cuticle...

BACKGROUND: Lumbar disc herniation (LDH) is a complex spinal disease, with multiple genetic polymorphisms being related to its risk. Nevertheless, the role of LINC-PINT polymorphisms in LDH risk has remained unknown. Therefore, this study aimed to investigate the association between LINC-PINT polymorphisms and LDH risk. METHODS: DNA was extracted from 504 LDH patients and 500 healthy controls. Three single nucleotide polymorphisms (SNPs) in LINC-PINT were selected and genotyped using Agena MassARRAY...

Cell motility is related to the higher-order structure of chromatin. Stimuli that induce cell migration change chromatin organization; such stimuli include elevated histone H3 lysine 9 trimethylation (H3K9me3). We previously showed that depletion of histone H3 lysine 9 methyltransferase, SUV39H1, suppresses directional cell migration. However, the molecular mechanism underlying this association between chromatin and cell migration remains elusive. The Golgi apparatus is a cell organelle essential for cell motility...

Oogenesis involves transduction of mechanical forces from the cytoskeleton to the nuclear envelope (NE). In Caenorhabditis elegans , oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to collapse under forces mediated through LINC (linker of nucleoskeleton and cytoskeleton) complexes. Here, we use cytological analysis and in vivo imaging to investigate the balance of forces that drive this collapse and protect oocyte nuclei. We also use a mechano-node-pore sensing device to directly measure the effect of genetic mutations on oocyte nuclear stiffness...

Plant cells lack centrosomes and instead utilise acentrosomal microtubule organising centres (MTOCs) to rapidly increase the number of microtubules at the onset of spindle assembly. Although several proteins required for MTOC formation have been identified, how the MTOC is positioned at the right place is not known. Here, we show that the inner nuclear membrane protein SUN2 is required for MTOC association with the nuclear envelope (NE) during mitotic prophase in the moss Physcomitrium patens. In actively dividing protonemal cells, microtubules accumulate around the NE during prophase...

The LINC complex, consisting of interacting SUN and KASH proteins, mechanically couples nuclear contents to the cytoskeleton. In meiosis, the LINC complex transmits microtubule-generated forces to chromosome ends, driving the rapid chromosome movements that are necessary for synapsis and crossing over. In somatic cells, it defines nuclear shape and positioning, and has a number of specialised roles, including hearing. Here, we report the X-ray crystal structure of a coiled-coiled domain of SUN1's luminal region, providing an architectural foundation for how SUN1 traverses the nuclear lumen, from the inner nuclear membrane to its interaction with KASH proteins at the outer nuclear membrane...

ADAD1 is a testis-specific RNA binding protein expressed in post-meiotic spermatids whose loss leads to defective sperm morphology and male infertility. However, the drivers of the Adad1 phenotype remain unclear. Morphological and functional analysis of Adad1 mutant sperm demonstrated defective DNA compaction, abnormal head shaping, and reduced motility. RNA sequencing of Adad1 mutant testes revealed minimal transcriptome changes however ribosome association of many transcripts was reduced, suggesting ADAD1 may be required for their translational activation...

Nuclear lamins have been considered an important structural element of the nucleus. The nuclear lamina is thought both to shield DNA from excessive mechanical forces and to transmit mechanical forces onto the DNA. However, to date there is not yet a technical approach to directly measure mechanical forces on nuclear lamins at the protein level. To overcome this limitation, we developed a nanobody-based intermolecular tension FRET biosensor capable of measuring the mechanical strain of lamin filaments. Using this sensor, we were able to show that the nuclear lamina is subjected to significant force...

OBJECTIVES: Cognitive analytic therapy (CAT) is used within UK mental health settings as a treatment for transdiagnostic complex psychological presentations. However, it is not routinely offered by the NHS Talking Therapies, for anxiety and depression (NHS Talking Therapies) programme which provides psychological treatments for common mental health difficulties. We aimed to evaluate the outcomes of providing CAT treatment to patients presenting with depression and/or anxiety, within the context of relational difficulties, adverse childhood experience or difficulty managing emotions, returning for further psychological treatment within NHS Talking Therapies...

The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon induction of unfolded protein responses (UPR) and are reduced upon activation of ER-phagy programs. A specialized domain of the ER, the nuclear envelope (NE), protects the cell genome with two juxtaposed lipid bilayers, the inner and outer nuclear membranes (INM and ONM) separated by the perinuclear space (PNS). Here we report that expansion of the mammalian ER upon homeostatic perturbations results in TMX4 reductase-driven disassembly of the LINC complexes connecting INM and ONM and in ONM swelling...