The LINC and NPC relationship – it's complicated!

ABSTRACT The genetic information of eukaryotic cells is enclosed within a double-layered nuclear envelope, which comprises an inner and outer nuclear membrane. Several transmembrane proteins locate to the nuclear envelope; however, only two integral protein complexes span the nuclear envelope and connect the inside of the nucleus to the cytoplasm. The nuclear pore complex (NPC) acts as a gateway for molecular exchange between the interior of the nucleus and the cytoplasm, whereas so-called LINC complexes physically link the nucleoskeleton and the cytoskeleton. In this Commentary, we will discuss recent studies that have established direct functional associations between these two complexes. The assembly of NPCs and their even distribution throughout the nuclear envelope is dependent on components of the LINC complex. Additionally, LINC complex formation is dependent on the successful localization of inner nuclear membrane components of LINC complexes and their transport through the NPC. Furthermore, the architecture of the nuclear envelope depends on both protein complexes. Finally, we will present recent evidence showing that LINC complexes can affect nucleo-cytoplasmic transport through the NPC, further highlighting the importance of understanding the associations of these essential complexes at the nuclear envelope. Summary: In this Commentary, we review for the first time, the functional associations of two integral members of the nuclear envelope, namely the linkers of the nucleoskeleton and cytoskeleton, and nuclear pore complexes.

[1]  M. Summers,et al.  Early sorting of inner nuclear membrane proteins is conserved , 2007, Proceedings of the National Academy of Sciences.

[2]  T. Misteli,et al.  Functional association of Sun1 with nuclear pore complexes , 2007, The Journal of cell biology.

[3]  A. Noegel,et al.  Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export , 2015, Nucleic acids research.

[4]  Tian Xu,et al.  SUN1/2 and Syne/Nesprin-1/2 Complexes Connect Centrosome to the Nucleus during Neurogenesis and Neuronal Migration in Mice , 2009, Neuron.

[5]  M. Hetzer,et al.  POM121 and Sun1 play a role in early steps of interphase NPC assembly , 2011, The Journal of cell biology.

[6]  I. Meier,et al.  Two Distinct Interacting Classes of Nuclear Envelope–Associated Coiled-Coil Proteins Are Required for the Tissue-Specific Nuclear Envelope Targeting of Arabidopsis RanGAP[W] , 2008, The Plant Cell Online.

[7]  Lixin Zhou,et al.  The nucleoporin Nup153 maintains nuclear envelope architecture and is required for cell migration in tumor cells , 2010, FEBS letters.

[8]  M. Hetzer,et al.  Nuclear Pores Form de Novo from Both Sides of the Nuclear Envelope , 2006, Science.

[9]  M. Mofrad,et al.  Evolutionarily Conserved Sequence Features Regulate the Formation of the FG Network at the Center of the Nuclear Pore Complex , 2015, Scientific Reports.

[10]  C. S. Chen,et al.  Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Jaspersen,et al.  Destination: inner nuclear membrane. , 2014, Trends in cell biology.

[12]  M. Goldberg,et al.  Relationships at the nuclear envelope: lamins and nuclear pore complexes in animals and plants. , 2010, Biochemical Society transactions.

[13]  M. Rexach,et al.  Discovering Novel Interactions at the Nuclear Pore Complex Using Bead Halo , 2008, Molecular & Cellular Proteomics.

[14]  Daniel A Starr,et al.  The Caenorhabditis elegans SUN protein UNC-84 interacts with lamin to transfer forces from the cytoplasm to the nucleoskeleton during nuclear migration , 2014, Molecular biology of the cell.

[15]  Andrea Rothballer,et al.  A classical NLS and the SUN domain contribute to the targeting of SUN2 to the inner nuclear membrane , 2010, The EMBO journal.

[16]  Daniel A Starr,et al.  KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus. , 2014, Current opinion in cell biology.

[17]  J. Aitchison,et al.  A Link between the Synthesis of Nucleoporins and the Biogenesis of the Nuclear Envelope , 2001, The Journal of cell biology.

[18]  Noémi Mészáros,et al.  Nuclear Pore Basket Proteins Are Tethered to the Nuclear Envelope and Can Regulate Membrane Curvature , 2015, Developmental cell.

[19]  Daniel A Starr,et al.  SUN proteins and nuclear envelope spacing , 2014, Nucleus.

[20]  Brian D. Slaughter,et al.  The SUN protein Mps3 controls Ndc1 distribution and function on the nuclear membrane , 2014, The Journal of cell biology.

[21]  Dirk Görlich,et al.  Structure of the metazoan Nup62.Nup58.Nup54 nucleoporin complex. , 2015 .

[22]  J. Köser,et al.  Distinct association of the nuclear pore protein Nup153 with A- and B-type lamins , 2011, Nucleus.

[23]  D. Görlich,et al.  Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles. , 2016, Trends in biochemical sciences.

[24]  P. Onck,et al.  Probing the disordered domain of the nuclear pore complex through coarse-grained molecular dynamics simulations. , 2014, Biophysical journal.

[25]  J. Holliday.  Sun , 1995 .

[26]  C. Stewart,et al.  A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton , 2013, The Journal of cell biology.

[27]  D. Evans,et al.  Characterization of SUN-domain proteins at the higher plant nuclear envelope. , 2010, The Plant journal : for cell and molecular biology.

[28]  C. Hoogenraad,et al.  Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry , 2010, PLoS biology.

[29]  Grant W. Brown,et al.  Functional Targeting of DNA Damage to a Nuclear Pore-Associated SUMO-Dependent Ubiquitin Ligase , 2008, Science.

[30]  M. Malumbres,et al.  Preparing a cell for nuclear envelope breakdown: Spatio‐temporal control of phosphorylation during mitotic entry , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[31]  Hans Janssen,et al.  Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin , 2005, The Journal of cell biology.

[32]  F. Pelegri,et al.  Localized Products of futile cycle/ lrmp Promote Centrosome-Nucleus Attachment in the Zebrafish Zygote , 2012, Current Biology.

[33]  Weidong Yang,et al.  Super-resolution 3D tomography of interactions and competition in the nuclear pore complex , 2016, Nature Structural &Molecular Biology.

[34]  Daniel A Starr,et al.  Multiple mechanisms actively target the SUN protein UNC-84 to the inner nuclear membrane , 2011, Molecular biology of the cell.

[35]  Jun Fan,et al.  A role for the spectrin superfamily member Syne-1 and kinesin II in cytokinesis , 2004, Journal of Cell Science.

[36]  M. Jantsch,et al.  Nuclear Envelope Retention of LINC Complexes Is Promoted by SUN-1 Oligomerization in the Caenorhabditis elegans Germ Line , 2016, Genetics.

[37]  G. Voeltz,et al.  Endoplasmic reticulum structure and interconnections with other organelles. , 2013, Cold Spring Harbor perspectives in biology.

[38]  O. Gavet,et al.  Activation of cyclin B1–Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis , 2010, The Journal of cell biology.

[39]  K. Wilson,et al.  The nuclear envelope at a glance , 2010, Journal of Cell Science.

[40]  Ulrike Kutay,et al.  The diverse functional LINCs of the nuclear envelope to the cytoskeleton and chromatin , 2013, Chromosoma.

[41]  A. Noegel,et al.  Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations , 2013, PloS one.

[42]  A. Fry,et al.  Mitotic phosphorylation of SUN1 loosens its connection with the nuclear lamina while the LINC complex remains intact , 2014, Nucleus.

[43]  I. Meier,et al.  Two Distinct Interacting Classes of Nuclear Envelope–Associated Coiled-Coil Proteins Are Required for the Tissue-Specific Nuclear Envelope Targeting of Arabidopsis RanGAP[W] , 2008, The Plant Cell Online.

[44]  G. Blobel,et al.  Structure of Nup58/45 Suggests Flexible Nuclear Pore Diameter by Intermolecular Sliding , 2007, Science.

[45]  R. Wozniak,et al.  Nup53 is required for nuclear envelope and nuclear pore complex assembly. , 2008, Molecular biology of the cell.

[46]  Daniel A Starr,et al.  The SUN protein UNC-84 is required only in force-bearing cells to maintain nuclear envelope architecture , 2014, The Journal of cell biology.

[47]  S. Jaspersen,et al.  Nuclear envelope insertion of spindle pole bodies and nuclear pore complexes , 2012, Nucleus.

[48]  D. Görlich,et al.  Systematic analysis of barrier-forming FG hydrogels from Xenopus nuclear pore complexes , 2012, The EMBO journal.

[49]  A. Noegel,et al.  Dictyostelium Sun‐1 Connects the Centrosome to Chromatin and Ensures Genome Stability , 2008, Traffic.

[50]  C. Feldherr,et al.  The permeability of the nuclear envelope in dividing and nondividing cell cultures , 1990, The Journal of cell biology.

[51]  Denis Wirtz,et al.  Dysfunctional connections between the nucleus and the actin and microtubule networks in laminopathic models. , 2008, Biophysical journal.

[52]  M. Mofrad,et al.  Rapid Brownian Motion Primes Ultrafast Reconstruction of Intrinsically Disordered Phe-Gly Repeats Inside the Nuclear Pore Complex , 2016, Scientific Reports.

[53]  J. Ellenberg,et al.  Sun1 forms immobile macromolecular assemblies at the nuclear envelope. , 2008, Biochimica et biophysica acta.

[54]  R. Heald,et al.  The RanGTP gradient – a GPS for the mitotic spindle , 2008, Journal of Cell Science.

[55]  J. Ahringer,et al.  The C. elegans Hook Protein, ZYG-12, Mediates the Essential Attachment between the Centrosome and Nucleus , 2003, Cell.

[56]  Daniel A Starr,et al.  UNC-83 IS a KASH protein required for nuclear migration and is recruited to the outer nuclear membrane by a physical interaction with the SUN protein UNC-84. , 2006, Molecular Biology of the Cell.

[57]  Min Han,et al.  KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development. , 2011, Human molecular genetics.

[58]  S. H. Mahboobi,et al.  The Interaction of CRM1 and the Nuclear Pore Protein Tpr , 2014, PloS one.

[59]  U. Kutay,et al.  Nuclear envelope localization of human UNC84A does not require nuclear lamins , 2006, FEBS letters.

[60]  A. Koide,et al.  Architecture of the fungal nuclear pore inner ring complex , 2015, Science.

[61]  Andrea Rothballer,et al.  Poring over pores: nuclear pore complex insertion into the nuclear envelope. , 2013, Trends in biochemical sciences.

[62]  Hengameh Shams,et al.  A Disulfide Bond Is Required for the Transmission of Forces through SUN-KASH Complexes. , 2015, Biophysical journal.

[63]  Sozanne R. Solmaz,et al.  Molecular Architecture of the Transport Channel of the Nuclear Pore Complex , 2011, Cell.

[64]  B. Chait,et al.  The molecular architecture of the nuclear pore complex , 2007, Nature.

[65]  M. Mofrad,et al.  On the Nuclear Pore Complex and Its Roles in Nucleo-Cytoskeletal Coupling and Mechanobiology , 2016 .

[66]  Xiulian Du,et al.  Structure of Sad1-UNC84 Homology (SUN) Domain Defines Features of Molecular Bridge in Nuclear Envelope* , 2011, The Journal of Biological Chemistry.

[67]  M. Mofrad,et al.  Higher Nucleoporin-Importinβ Affinity at the Nuclear Basket Increases Nucleocytoplasmic Import , 2013, PloS one.

[68]  D. Cowburn,et al.  The molecular mechanism of nuclear transport revealed by atomic-scale measurements , 2015, eLife.

[69]  M. Mofrad,et al.  Nucleoporin's Like Charge Regions Are Major Regulators of FG Coverage and Dynamics Inside the Nuclear Pore Complex , 2015, PloS one.

[70]  W. Gong,et al.  Coiled-Coil Domains of SUN Proteins as Intrinsic Dynamic Regulators. , 2016, Structure.

[71]  Yixian Zheng,et al.  Lamins position the nuclear pores and centrosomes by modulating dynein , 2015, Molecular biology of the cell.

[72]  O. Medalia,et al.  The human nuclear pore complex as revealed by cryo-electron tomography. , 2012, Structure.

[73]  P. Bork,et al.  In situ structural analysis of the human nuclear pore complex , 2015, Nature.

[74]  U. Kutay,et al.  Structural insights into LINC complexes. , 2013, Current opinion in structural biology.

[75]  Andrea Rothballer,et al.  LINC Complexes Form by Binding of Three KASH Peptides to Domain Interfaces of Trimeric SUN Proteins , 2012, Cell.

[76]  U. Kutay,et al.  Orchestrating nuclear envelope disassembly and reassembly during mitosis , 2009, Nature Reviews Molecular Cell Biology.

[77]  M. Mofrad,et al.  Nuclear pore complex: biochemistry and biophysics of nucleocytoplasmic transport in health and disease. , 2011, International review of cell and molecular biology.

[78]  M. Yanagida,et al.  The product of the spindle formation gene sad1+ associates with the fission yeast spindle pole body and is essential for viability , 1995, The Journal of cell biology.

[79]  C. Shanahan,et al.  Nesprins: from the nuclear envelope and beyond , 2013, Expert Reviews in Molecular Medicine.

[80]  Ruedi Aebersold,et al.  Phosphorylation of Nup98 by Multiple Kinases Is Crucial for NPC Disassembly during Mitotic Entry , 2011, Cell.

[81]  Yousef Jamali,et al.  Brownian Dynamics Simulation of Nucleocytoplasmic Transport: A Coarse-Grained Model for the Functional State of the Nuclear Pore Complex , 2011, PLoS Comput. Biol..

[82]  I. Meier,et al.  Novel plant SUN–KASH bridges are involved in RanGAP anchoring and nuclear shape determination , 2012, The Journal of cell biology.

[83]  Min Han,et al.  Inner Nuclear Envelope Proteins SUN1 and SUN2 Play a Prominent Role in the DNA Damage Response , 2012, Current Biology.

[84]  T. Schwartz,et al.  The nuclear pore complex – structure and function at a glance , 2015, Journal of Cell Science.

[85]  B. Vollmer,et al.  Nup153 Recruits the Nup107-160 Complex to the Inner Nuclear Membrane for Interphasic Nuclear Pore Complex Assembly. , 2015, Developmental cell.

[86]  G. Blobel,et al.  Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex , 2015, Cell.

[87]  Min Han,et al.  SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice , 2009, Proceedings of the National Academy of Sciences.

[88]  Joshua L. Phillips,et al.  A Bimodal Distribution of Two Distinct Categories of Intrinsically Disordered Structures with Separate Functions in FG Nucleoporins* , 2010, Molecular & Cellular Proteomics.

[89]  T. Kieselbach,et al.  Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance , 2009, The Journal of cell biology.

[90]  Ohad Medalia,et al.  Functional architecture of the nuclear pore complex. , 2012, Annual review of biophysics.

[91]  G. Blobel,et al.  SUMO-1 Modification and Its Role in Targeting the Ran GTPase-activating Protein, RanGAP1, to the Nuclear Pore Complex , 1998, The Journal of cell biology.

[92]  A. Méjat.  LINC complexes in health and disease , 2010, Nucleus.

[93]  Wolfram Antonin,et al.  The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells. , 2006, Molecular cell.

[94]  N. Pante,et al.  Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. , 2002, Molecular biology of the cell.

[95]  U. Kutay,et al.  SUN proteins facilitate the removal of membranes from chromatin during nuclear envelope breakdown , 2014, The Journal of cell biology.

[96]  D. Botstein,et al.  NDC1: a nuclear periphery component required for yeast spindle pole body duplication , 1993, The Journal of cell biology.

[97]  Min Han,et al.  A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis , 2012, The Journal of cell biology.

[98]  B. Maček,et al.  Dimerization and direct membrane interaction of Nup53 contribute to nuclear pore complex assembly , 2012, The EMBO journal.

[99]  S. Jaspersen,et al.  Targeting of the SUN protein Mps3 to the inner nuclear membrane by the histone variant H2A.Z , 2011, The Journal of cell biology.

[100]  David Ando,et al.  Physical Motif Clustering within Intrinsically Disordered Nucleoporin Sequences Reveals Universal Functional Features , 2013, PloS one.

[101]  J. Ellenberg,et al.  A Nup133-dependent NPC-anchored network tethers centrosomes to the nuclear envelope in prophase , 2011, The Journal of cell biology.

[102]  A. Hoelz,et al.  Architecture of the symmetric core of the nuclear pore , 2016, Science.

[103]  A. Noegel,et al.  The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope , 2005, Journal of Cell Science.

[104]  J. Lammerding,et al.  The Interaction between Nesprins and Sun Proteins at the Nuclear Envelope Is Critical for Force Transmission between the Nucleus and Cytoskeleton* , 2011, The Journal of Biological Chemistry.

[105]  M. Blackledge,et al.  Plasticity of an Ultrafast Interaction between Nucleoporins and Nuclear Transport Receptors , 2015, Cell.

[106]  M. Mofrad,et al.  On the octagonal structure of the nuclear pore complex: insights from coarse-grained models. , 2008, Biophysical journal.

[107]  C. Stewart,et al.  Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization , 2009, Proceedings of the National Academy of Sciences.

[108]  Qian Liu,et al.  Citation for Published Item: Use Policy Coupling of the Nucleus and Cytoplasm: Role of the Linc Complex , 2022 .

[109]  Sozanne R. Solmaz,et al.  Ring cycle for dilating and constricting the nuclear pore , 2013, Proceedings of the National Academy of Sciences.

[110]  O. Niwa,et al.  Two-hybrid search for proteins that interact with Sad1 and Kms1, two membrane-bound components of the spindle pole body in fission yeast , 2004, Molecular Genetics and Genomics.

[111]  W. Antonin,et al.  Interaction of Nup53 with Ndc1 and Nup155 is required for nuclear pore complex assembly , 2014, Journal of Cell Science.

[112]  M. D'Angelo,et al.  Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions , 2012, Nature Reviews Molecular Cell Biology.