Nuclear envelope

The nuclear envelope is made up of two lipid bilayer membranes, an inner nuclear membrane and an outer nuclear membrane. These membranes are connected to each other by nuclear pores. Two sets of intermediate filaments provide support for the nuclear envelope. An internal network forms the nuclear lamina on the inner nuclear membrane.{{cite journal|last1=Coutinho|first1=Henrique Douglas M|last2=Falcão-Silva|first2=Vivyanne S|last3=Gonçalves|first3=Gregório Fernandes|last4=da Nóbrega|first4=Raphael Batista|title=Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model|journal=Immunity & Ageing|volume=6|pages=4|doi=10.1186/1742-4933-6-4|pmid=19379495|pmc=2674425|date=20 April 2009 |doi-access=free }} A looser network forms outside to give external support. The actual shape of the nuclear envelope is irregular. It has invaginations and protrusions and can be observed with an electron microscope.

File:Nuclear envelope of one cancerous HeLa cell.png. The cell was observed in 300 slices of electron microscopy, the nuclear envelope was automatically segmented and rendered. One vertical and one horizontal slice are added for reference.]]

The outer nuclear membrane also shares a common border with the endoplasmic reticulum.{{cite web|title=Chloride channels in the Nuclear membrane|url=http://clapham.tch.harvard.edu/publications/pdf/Tabares_JMB_91.pdf|publisher=Harvard.edu|access-date=7 December 2012|archive-url=https://web.archive.org/web/20100802223435/http://clapham.tch.harvard.edu/publications/pdf/Tabares_JMB_91.pdf|archive-date=2 August 2010|url-status=dead}} While it is physically linked, the outer nuclear membrane contains proteins found in far higher concentrations than the endoplasmic reticulum.{{cite journal|last=Hetzer|first=Mertin|title=The Nuclear Envelope|journal=Cold Spring Harbor Perspectives in Biology|date=February 3, 2010|pmc=2829960|pmid=20300205|doi=10.1101/cshperspect.a000539|volume=2|issue=3|pages=a000539}} All four nesprin proteins (nuclear envelope spectrin repeat proteins) present in mammals are expressed in the outer nuclear membrane.{{Cite journal|last1=Wilson|first1=Katherine L.|last2=Berk|first2=Jason M.|date=2010-06-15|title=The nuclear envelope at a glance|journal=J Cell Sci|language=en|volume=123|issue=12|pages=1973–1978|doi=10.1242/jcs.019042|issn=0021-9533|pmc=2880010|pmid=20519579}} Nesprin proteins connect cytoskeletal filaments to the nucleoskeleton.{{Cite journal|last1=Burke|first1=Brian|last2=Roux|first2=Kyle J.|date=2009-11-01|title=Nuclei take a position: managing nuclear location|journal=Developmental Cell|volume=17|issue=5|pages=587–597|doi=10.1016/j.devcel.2009.10.018|issn=1878-1551|pmid=19922864|doi-access=free}} Nesprin-mediated connections to the cytoskeleton contribute to nuclear positioning and to the cell’s mechanosensory function.{{Cite journal|last1=Uzer|first1=Gunes|last2=Thompson|first2=William R.|last3=Sen|first3=Buer|last4=Xie|first4=Zhihui|last5=Yen|first5=Sherwin S.|last6=Miller|first6=Sean|last7=Bas|first7=Guniz|last8=Styner|first8=Maya|last9=Rubin|first9=Clinton T.|date=2015-06-01|title=Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus|journal=Stem Cells|language=en|volume=33|issue=6|pages=2063–2076|doi=10.1002/stem.2004|issn=1066-5099|pmc=4458857|pmid=25787126}} KASH domain proteins of Nesprin-1 and -2 are part of a LINC complex (linker of nucleoskeleton and cytoskeleton) and can bind directly to cystoskeletal components, such as actin filaments, or can bind to proteins in the perinuclear space.{{Cite journal|last1=Crisp|first1=Melissa|last2=Liu|first2=Qian|last3=Roux|first3=Kyle|last4=Rattner|first4=J. B.|last5=Shanahan|first5=Catherine|last6=Burke|first6=Brian|last7=Stahl|first7=Phillip D.|last8=Hodzic|first8=Didier|date=2006-01-02|title=Coupling of the nucleus and cytoplasm: role of the LINC complex|journal=The Journal of Cell Biology|volume=172|issue=1|pages=41–53|doi=10.1083/jcb.200509124|issn=0021-9525|pmc=2063530|pmid=16380439}}{{cite journal|last1=Zeng |display-authors=etal |first1=X|title=Nuclear Envelope-Associated Chromosome Dynamics during Meiotic Prophase I.|journal=Frontiers in Cell and Developmental Biology|volume=5|pages=121|doi=10.3389/fcell.2017.00121|pmid=29376050|pmc=5767173|year=2018 |doi-access=free }} Nesprin-3 and -4 may play a role in unloading enormous cargo; Nesprin-3 proteins bind plectin and link the nuclear envelope to cytoplasmic intermediate filaments.{{Cite journal|last1=Wilhelmsen|first1=Kevin|last2=Litjens|first2=Sandy H. M.|last3=Kuikman|first3=Ingrid|last4=Tshimbalanga|first4=Ntambua|last5=Janssen|first5=Hans|last6=van den Bout|first6=Iman|last7=Raymond|first7=Karine|last8=Sonnenberg|first8=Arnoud|date=2005-12-05|title=Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin|journal=The Journal of Cell Biology|volume=171|issue=5|pages=799–810|doi=10.1083/jcb.200506083|issn=0021-9525|pmc=2171291|pmid=16330710}} Nesprin-4 proteins bind the plus end directed motor kinesin-1.{{Cite journal|last1=Roux|first1=Kyle J.|last2=Crisp|first2=Melissa L.|last3=Liu|first3=Qian|last4=Kim|first4=Daein|last5=Kozlov|first5=Serguei|last6=Stewart|first6=Colin L.|last7=Burke|first7=Brian|date=2009-02-17|title=Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=7|pages=2194–2199|doi=10.1073/pnas.0808602106|issn=1091-6490|pmc=2650131|pmid=19164528|bibcode=2009PNAS..106.2194R|doi-access=free}} The outer nuclear membrane is also involved in development, as it fuses with the inner nuclear membrane to form nuclear pores.{{Cite journal|last1=Fichtman|first1=Boris|last2=Ramos|first2=Corinne|last3=Rasala|first3=Beth|last4=Harel|first4=Amnon|last5=Forbes|first5=Douglass J.|date=2010-12-01|title=Inner/Outer Nuclear Membrane Fusion in Nuclear Pore Assembly|journal=Molecular Biology of the Cell|volume=21|issue=23|pages=4197–4211|doi=10.1091/mbc.E10-04-0309|issn=1059-1524|pmc=2993748|pmid=20926687}}

{{Further |Inner nuclear membrane proteins}}

The inner nuclear membrane encloses the nucleoplasm, and is covered by the nuclear lamina, a mesh of intermediate filaments which stabilizes the nuclear membrane as well as being involved in chromatin function. It is connected to the outer membrane by nuclear pores which penetrate the membranes. While the two membranes and the endoplasmic reticulum are linked, proteins embedded in the membranes tend to stay put rather than dispersing across the continuum.{{cite journal|title=The inner nuclear membrane: simple, or very complex?|journal=The EMBO Journal|date=April 19, 2001|volume=20|issue=12|doi=10.1093/emboj/20.12.2989|pmid=11406575|pmc=150211|pages=2989–2994|last1=Georgatos|first1=S. D.}} It is lined with a fiber network called the nuclear lamina which is 10-40 nm thick and provides strength.{{Citation needed|date=December 2021}}

Mutations in the genes that encode for the inner nuclear membrane proteins can cause several laminopathies.{{cn|date=March 2023}}

{{main|Nuclear pore|Nuclear pore complex}}

File:Endomembrane system diagram en.svg

The nuclear envelope is punctured by around a thousand nuclear pore complexes, about 100 nm across, with an inner channel about 40 nm wide. The complexes contain a number of nucleoporins, proteins that link the inner and outer nuclear membranes.{{cn|date=March 2023}}

During the G2 phase of interphase, the nuclear membrane increases its surface area and doubles its number of nuclear pore complexes.

In eukaryotes such as yeast which undergo closed mitosis, the nuclear membrane stays intact during cell division. The spindle fibers either form within the membrane, or penetrate it without tearing it apart.

In other eukaryotes (animals as well as plants), the nuclear membrane must break down during the prometaphase stage of mitosis to allow the mitotic spindle fibers to access the chromosomes inside. The breakdown and reformation processes are not well understood.

File:Nuclear_envelope_breakdown_and_reassembly_in_mitosis.jpg]]

In mammals, the nuclear membrane can break down within minutes, following a set of steps during the early stages of mitosis.

First, M-Cdk's phosphorylate nucleoporin polypeptides and they are selectively removed from the nuclear pore complexes. After that, the rest of the nuclear pore complexes break apart simultaneously. Biochemical evidence suggests that the nuclear pore complexes disassemble into stable pieces rather than disintegrating into small polypeptide fragments. M-Cdk's also phosphorylate elements of the nuclear lamina (the framework that supports the envelope) leading to the disassembly of the lamina and hence the envelope membranes into small vesicles.{{cite book|last=Alberts |display-authors=etal|title=Molecular Biology of The Cell|year=2008|publisher=Garland Science|location=New York|isbn=978-0-8153-4106-2|pages=1079–1080|edition= 5th|chapter=Chapter 17: The Cell Cycle}}

Electron and fluorescence microscopy has given strong evidence that the nuclear membrane is absorbed by the endoplasmic reticulum—nuclear proteins not normally found in the endoplasmic reticulum show up during mitosis.

In addition to the breakdown of the nuclear membrane during the prometaphase stage of mitosis, the nuclear membrane also ruptures in migrating mammalian cells during the interphase stage of the cell cycle.{{cite journal |vauthors=Raab M, Gentili M, de Belly H, Thiam HR, Vargas P, Jimenez AJ, Lautenschlaeger F, Voituriez R, Lennon-Duménil AM, Manel N, Piel M |title=ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death |journal=Science |volume=352 |issue=6283 |pages=359–62 |year=2016 |pmid=27013426 |doi=10.1126/science.aad7611 |bibcode=2016Sci...352..359R |s2cid=28544308 }} This transient rupture is likely caused by nuclear deformation. The rupture is rapidly repaired by a process dependent on "endosomal sorting complexes required for transport" (ESCRT) made up of cytosolic protein complexes. During nuclear membrane rupture events, DNA double-strand breaks occur. Thus the survival of cells migrating through confined environments appears to depend on efficient nuclear envelope and DNA repair machineries.

Aberrant nuclear envelope breakdown has also been observed in laminopathies and in cancer cells leading to mislocalization of cellular proteins, the formation of micronuclei and genomic instability.{{cite journal |last1=Vargas |display-authors=etal|title=Transient nuclear envelope rupturing during interphase in human cancer cells |journal=Nucleus (Austin, Tex.)|volume=3|issue=1|pages=88–100|publisher=Nucleus |pmc=3342953|year=2012|pmid=22567193|doi=10.4161/nucl.18954}}{{cite journal |last1=Lim |display-authors=etal|title=Nuclear envelope rupture drives genome instability in cancer |journal=Molecular Biology of the Cell|volume=27|issue=21|pages=3210–3213|publisher=MBoC |pmc=5170854|year=2016|pmid=27799497|doi=10.1091/mbc.E16-02-0098}}{{cite journal |last1=Hatch |display-authors=etal|title=Nuclear envelope rupture is induced by actin-based nucleus confinement |volume=215|issue=1|pages=27–36|url=http://jcb.rupress.org/content/215/1/27 |journal=Journal of Cell Biology |publisher=JCB |access-date=24 March 2019|pmid=27697922|year=2016|doi=10.1083/jcb.201603053|pmc=5057282}}

Exactly how the nuclear membrane reforms during telophase of mitosis is debated. Two theories exist—

• Vesicle fusion — where vesicles of nuclear membrane fuse together to rebuild the nuclear membrane
• Re-shaping of the endoplasmic reticulum—where the parts of the endoplasmic reticulum containing the absorbed nuclear membrane envelop the nuclear space, reforming a closed membrane.

A study of the comparative genomics, evolution and origins of the nuclear membrane led to the proposal that the nucleus emerged in the primitive eukaryotic ancestor (the “prekaryote”), and was triggered by the archaeo-bacterial symbiosis.{{cite journal |vauthors=Mans BJ, Anantharaman V, Aravind L, Koonin EV |title=Comparative genomics, evolution and origins of the nuclear envelope and nuclear pore complex |journal=Cell Cycle |volume=3 |issue=12 |pages=1612–37 |year=2004 |pmid=15611647 |doi=10.4161/cc.3.12.1316 |doi-access=free }} Several ideas have been proposed for the evolutionary origin of the nuclear membrane.{{cite journal |vauthors=Martin W |title=Archaebacteria (Archaea) and the origin of the eukaryotic nucleus |journal=Curr. Opin. Microbiol. |volume=8 |issue=6 |pages=630–7 |year=2005 |pmid=16242992 |doi=10.1016/j.mib.2005.10.004 }} These ideas include the invagination of the plasma membrane in a prokaryote ancestor, or the formation of a genuine new membrane system following the establishment of proto-mitochondria in the archaeal host. The adaptive function of the nuclear membrane may have been to serve as a barrier to protect the genome from reactive oxygen species (ROS) produced by the cells' pre-mitochondria.{{cite journal |vauthors=Speijer D |title=Birth of the eukaryotes by a set of reactive innovations: New insights force us to relinquish gradual models |journal=BioEssays |volume=37 |issue=12 |pages=1268–76 |year=2015 |pmid=26577075 |doi=10.1002/bies.201500107 |s2cid=20068849 }}Bernstein H, Bernstein C. Sexual communication in archaea, the precursor to meiosis. pp. 103-117 in Biocommunication of Archaea (Guenther Witzany, ed.) 2017. Springer International Publishing {{ISBN|978-3-319-65535-2}} DOI 10.1007/978-3-319-65536-9

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{{Reflist}}

{{Commons category|Nuclear membranes}}

• {{BUHistology|20102loa}}
• [http://sspatel.googlepages.com/nuclearporecomplex Animations of nuclear pores and transport through the nuclear envelope] {{Webarchive|url=https://web.archive.org/web/20090207201940/http://sspatel.googlepages.com/nuclearporecomplex |date=2009-02-07 }}
• [http://sspatel.googlepages.com/nuclearporecomplex2 Illustrations of nuclear pores and transport through the nuclear membrane] {{Webarchive|url=https://web.archive.org/web/20090207214312/http://sspatel.googlepages.com/nuclearporecomplex2 |date=2009-02-07 }}
• {{MeshName|Nuclear+membrane}}

{{Structures of the cell membrane}}

{{Nucleus}}

{{Authority control}}

Category:Membrane biology

Category:Nuclear substructures