Nuclear bodies

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Nuclear bodies in human embryonic lung cells HEL cells + PML3 eCFP.png
Nuclear bodies in human embryonic lung cells

Nuclear bodies (also known as nuclear domains or nuclear dots) are biomolecular condensates, membraneless structures found in the cell nuclei of eukaryotic cells. [1] Nuclear bodies include Cajal bodies, the nucleolus, nuclear speckles (also called splicing speckles), histone locus bodies, and promyelocytic leukemia protein (PML) nuclear bodies (also called PML oncogenic dots). [2] Nuclear bodies also include ND10s. ND stands for nuclear domain, and 10 refers to the number of dots seen. [3] Additionally, a nuclear body subtype is a clastosome suggested to be a site of protein degradation. [4]

Contents

While biomolecular condensate is a term often used interchangeably with nuclear bodies, the term "condensates" implies the thermodynamic properties of the body are known. [5] Thus, nuclear body (and sometimes nuclear compartment) is a term that is more general and encompasses structures where either the biophysical property is not a condensate or is currently untested. [6]

Nuclear bodies were first seen as prominent interchromatin structures in the nuclei of malignant or hyperstimulated animal cells [7] [8] identified using anti-sp100 autoantibodies from primary biliary cirrhosis and subsequently the promyelocytic leukemia (PML) factor, but appear also to be elevated in many autoimmune and cancerous diseases. [9] Nuclear dots are metabolically stable and resistant to nuclease digestion and salt extraction. [10]

Structure

Diagram of the formation of nuclear bodies. Formation and examples of nuclear membraneless compartments.png
Diagram of the formation of nuclear bodies.

Simple nuclear bodies (types I and II) and the shells of complex nuclear bodies (types III, IVa and V) consist of a non-chromatinic fibrillar material which is most likely proteinaceous. [11] That nuclear bodies co-isolated with the nuclear matrix, and were linked to the fibrogranular nuclear matrix component by projections from the surface of the nuclear bodies. [11] The primary components of the nuclear dots are the proteins sp100 nuclear antigen, LYSP100(a homolog of sp100), [12] ISG20, [13] PML antigen, NDP55 and 53kDa protein associated with the nuclear matrix. [14] Other proteins, such as PIC1/SUMO-1, which are associated with nuclear pore complex also associate with nuclear dots. [15] The proteins can reorganize in the nucleus, by increasing number of dispersion in response to different stress (stimulation or heat shock, respectively). [16]

Function

One of the nuclear body proteins appears to be involved in transcriptional active regions. [17] Expression of PML antigen and sp100 is responsive to interferons. Sp100 seems to have transcriptional transactivating properties. PML protein was reported to suppress growth and transformation, [8] and specifically inhibits the infection of vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus, [18] but not other types of viruses. The SUMO-1 ubiquitin like protein is responsible for modifying PML protein such that it is targeted to dots. [19] whereas overexpression of PML results in programmed cell death. [20]

One hypothesized function of the dots is as a 'nuclear dump' or 'storage depot'. [21] The nuclear bodies may not all perform the same function. Sp140 associates with certain bodies and appears to be involved in transcriptional activation. [22]

ND10 nuclear bodies have been shown to play a major role in chromatin regulation. [23]

Nuclear bodies have been suggested to be involved in multiple aspects of gene regulation. By concentrating substrates and enzymes in these defined territories (i.e., pre-ribosomal RNA and associated ribosome biogenesis protein within the nucleolus), it is hypothesized that this may help increase the efficiency of the enzymatic reactions associated with the particular nuclear body. For example, nuclear speckles, once thought to be storage depots of splicing factors, have been now shown to concentrate splicing-promoting factors (e.g., components of the major and minor spliceosome) and pre-mRNA substrate molecules to boost the kinetic efficiency of the splicing reaction. [24] Thus future studies will show whether other nuclear bodies play functional roles in various aspects of gene regulation, such as transcription, RNA modifications, ribosome biogenesis, and other nuclear processes.

Pathology

Immunofluorescence staining pattern of sp100 antibodies. Nuclear dots can be seen in the nucleus of the cells. Produced using serum from a patient with primary biliary cirrhosis on HEp-20-10 cells with a FITC conjugate. ANA NUCLEAR DOT AND AMA.jpg
Immunofluorescence staining pattern of sp100 antibodies. Nuclear dots can be seen in the nucleus of the cells. Produced using serum from a patient with primary biliary cirrhosis on HEp-20-10 cells with a FITC conjugate.

These, or similar, bodies have been found increased in the presence of lymphoid cancers [25] [26] and SLE (lupus). [27] They are also observed at higher frequencies in subacute sclerosing panencephalitis; in this instance, antibodies to measles show expression in and localization to the nuclear bodies. [28]

Related Research Articles

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The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.

<span class="mw-page-title-main">Acute promyelocytic leukemia</span> Subtype of acute myeloid leukaemia characterised by accumulation of promyelocytes

Acute promyelocytic leukemia is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.

<span class="mw-page-title-main">HHV Infected Cell Polypeptide 0</span> Protein

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.

<span class="mw-page-title-main">Death-associated protein 6</span> Protein found in humans

Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the DAXX gene.

<span class="mw-page-title-main">HDAC1</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.

<span class="mw-page-title-main">Nuclear receptor co-repressor 1</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.

<span class="mw-page-title-main">Nuclear receptor co-repressor 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 2 (NCOR2) is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression. NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT) or T3 receptor-associating cofactor 1 (TRAC-1).

<span class="mw-page-title-main">Nuclear receptor 4A1</span> Mammalian protein found in Homo sapiens

The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.

Sp100 nuclear antigen is an interferon stimulated antigen found in the cell nuclei of many human and higher animal cells. Autoantibodies directed against Sp100 are often found in patients with primary biliary cirrhosis. Histologically Sp100 'dots' regions of the cell nucleus. Viral infection and mitogens affect the expression of the Sp100 autoantigen. Cells grown in the presence of interferons revealed an increase both in size and number of the Sp100 protein-containing nuclear dots and increase the protein concentration. This raises "the question whether cytokine-mediated increase of Sp100 protein expression plays a role in induction of anti-Sp100 autoantibodies."

<span class="mw-page-title-main">Promyelocytic leukemia protein</span> Protein found in humans

Promyelocytic leukemia protein (PML) is the protein product of the PML gene. PML protein is a tumor suppressor protein required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the chromatin of the cell nucleus. These nuclear bodies are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in programmed cell death, genome stability, antiviral effects and controlling cell division. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

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<span class="mw-page-title-main">GATA2</span> Protein found in humans

GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.

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<span class="mw-page-title-main">SP110</span> Protein-coding gene in the species Homo sapiens

SP110 nuclear body protein is a protein that in humans is encoded by the SP110 gene.

<span class="mw-page-title-main">PRAM1</span> Protein-coding gene in the species Homo sapiens

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The RARA gene, also known as NR1B1, is a protein coding gene located on chromosome 17 that provides the instructions required to make transcription factor Retinoic Acid Receptor Alpha.

References

  1. ↑ Weber SC (June 2017). "Sequence-encoded material properties dictate the structure and function of nuclear bodies". Current Opinion in Cell Biology. 46: 62–71. doi:10.1016/j.ceb.2017.03.003. PMID   28343140.
  2. ↑ Zimber A, Nguyen QD, Gespach C (October 2004). "Nuclear bodies and compartments: functional roles and cellular signalling in health and disease". Cellular Signalling. 16 (10): 1085–104. doi:10.1016/j.cellsig.2004.03.020. PMID   15240004.
  3. ↑ Rivera-Molina YA, Martínez FP, Tang Q (August 2013). "Nuclear domain 10 of the viral aspect". World Journal of Virology. 2 (3): 110–22. doi: 10.5501/wjv.v2.i3.110 . PMC   3832855 . PMID   24255882.
  4. ↑ Lafarga M, Berciano MT, Pena E, Mayo I, Castaño JG, Bohmann D, et al. (August 2002). "Clastosome: a subtype of nuclear body enriched in 19S and 20S proteasomes, ubiquitin, and protein substrates of proteasome". Molecular Biology of the Cell. 13 (8): 2771–82. doi:10.1091/mbc.e02-03-0122. PMC   117941 . PMID   12181345.
  5. ↑ Banani SF, Lee HO, Hyman AA, Rosen MK (May 2017). "Biomolecular condensates: organizers of cellular biochemistry". Nature Reviews. Molecular Cell Biology. 18 (5): 285–298. doi:10.1038/nrm.2017.7. PMC   7434221 . PMID   28225081. S2CID   37694361.
  6. ↑ Bhat P, Hanson D, Guttman M (August 2021). "Nuclear compartmentalization as a mechanism for quantitative control of gene expression". Nature Reviews. Molecular Cell Biology. 22 (5): 653–670. doi:10.1038/s41580-021-00387-1. PMID   34341548.
  7. ↑ Brasch K, Ochs RL (October 1992). "Nuclear bodies (NBs): a newly "rediscovered" organelle". Experimental Cell Research. 202 (2): 211–23. doi:10.1016/0014-4827(92)90068-J. PMID   1397076.
  8. 1 2 Sternsdorf T, Grötzinger T, Jensen K, Will H (December 1997). "Nuclear dots: actors on many stages". Immunobiology. 198 (1–3): 307–31. doi:10.1016/s0171-2985(97)80051-4. PMID   9442402.
  9. ↑ Pawlotsky JM, Andre C, Metreau JM, Beaugrand M, Zafrani ES, Dhumeaux D (July 1992). "Multiple nuclear dots antinuclear antibodies are not specific for primary biliary cirrhosis". Hepatology. 16 (1): 127–31. doi:10.1002/hep.1840160121. PMID   1319948. S2CID   22729443.
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  11. 1 2 Chaly N, Setterfield G, Kaplan JG, Brown DL (1983). "Nuclear bodies in mouse splenic lymphocytes: II - Cytochemistry and autoradiography during stimulation by concanavalin A". Biology of the Cell. 49 (1): 35–43. doi:10.1111/j.1768-322x.1984.tb00220.x. PMID   6199062. S2CID   43084163.
  12. ↑ Dent AL, Yewdell J, Puvion-Dutilleul F, Koken MH, de The H, Staudt LM (August 1996). "LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies". Blood. 88 (4): 1423–6. doi: 10.1182/blood.V88.4.1423.bloodjournal8841423 . PMID   8695863.
  13. ↑ Gongora C, David G, Pintard L, Tissot C, Hua TD, Dejean A, Mechti N (August 1997). "Molecular cloning of a new interferon-induced PML nuclear body-associated protein". The Journal of Biological Chemistry. 272 (31): 19457–63. doi: 10.1074/jbc.272.31.19457 . PMID   9235947.
  14. ↑ Zuber M, Heyden TS, Lajous-Petter AM (1995). "A human autoantibody recognizing nuclear matrix-associated nuclear protein localized in dot structures". Biology of the Cell. 85 (1): 77–86. doi:10.1111/j.1768-322X.1995.tb00944.x. PMID   8882521.
  15. ↑ Sternsdorf T, Jensen K, Will H (December 1997). "Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1". The Journal of Cell Biology. 139 (7): 1621–34. doi:10.1083/jcb.139.7.1621. PMC   2132645 . PMID   9412458.
  16. ↑ Maul GG, Yu E, Ishov AM, Epstein AL (December 1995). "Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress". Journal of Cellular Biochemistry. 59 (4): 498–513. doi:10.1002/jcb.240590410. PMID   8749719. S2CID   22209911.
  17. ↑ Xie K, Lambie EJ, Snyder M (October 1993). "Nuclear dot antigens may specify transcriptional domains in the nucleus". Molecular and Cellular Biology. 13 (10): 6170–9. doi:10.1128/MCB.13.10.6170. PMC   364676 . PMID   8413218.
  18. ↑ Chelbi-Alix MK, Quignon F, Pelicano L, Koken MH, de Thé H (February 1998). "Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein". Journal of Virology. 72 (2): 1043–51. doi:10.1128/JVI.72.2.1043-1051.1998. PMC   124576 . PMID   9444998.
  19. 1 2 Müller S, Matunis MJ, Dejean A (January 1998). "Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus". The EMBO Journal. 17 (1): 61–70. doi:10.1093/emboj/17.1.61. PMC   1170358 . PMID   9427741.
  20. ↑ Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de Thé H (November 1998). "PML induces a novel caspase-independent death process". Nature Genetics. 20 (3): 259–65. doi:10.1038/3068. PMID   9806544. S2CID   856232.
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  22. ↑ Bloch DB, Chiche JD, Orth D, de la Monte SM, Rosenzweig A, Bloch KD (June 1999). "Structural and functional heterogeneity of nuclear bodies". Molecular and Cellular Biology. 19 (6): 4423–30. doi:10.1128/MCB.19.6.4423. PMC   104401 . PMID   10330182.
  23. ↑ Gu H, Zheng Y (April 2016). "Role of ND10 nuclear bodies in the chromatin repression of HSV-1". Virology Journal. 13: 62. doi: 10.1186/s12985-016-0516-4 . PMC   4822283 . PMID   27048561.
  24. ↑ Bhat P, Chow A, Emert B, et al. (May 2024). "Genome organization around nuclear speckles drives mRNA splicing efficiency". Nature. 629 (5): 1165–1173. doi:10.1038/s41586-024-07429-6. PMC   11164319 . PMID   38720076.
  25. ↑ Rivas C, Oliva H (1974). "Nuclear bodies in Hodgkin's disease". Pathologia Europaea. 9 (4): 297–301. PMID   4457783.
  26. ↑ Tani E, Ametani T (1975). "Nuclear Characteristics of Malignant Lymphoma in the Brain". Malignant Lymphomas of the Nervous System. Vol. Suppl 6. pp. 167–71. doi:10.1007/978-3-662-08456-4_28. ISBN   978-3-540-07208-9. PMID   168720.{{cite book}}: |journal= ignored (help)
  27. ↑ Jones JM, Martinez AJ, Joshi VV, McWilliams N (March 1975). "Systemic lupus erythematosus". Archives of Pathology. 99 (3): 152–7. PMID   164172.
  28. ↑ Brown HR, Thormar H (November 1976). "Immunoperoxidase staining of simple nuclear bodies in sclerosing panencephalitis (SSPE) by antiserum to Measles nucleocapsids". Acta Neuropathologica. 36 (3): 259–67. doi:10.1007/BF00685370. PMID   795259. S2CID   38057985.
  29. ↑ Nervi C, Ferrara FF, Fanelli M, Rippo MR, Tomassini B, Ferrucci PF, et al. (October 1998). "Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein". Blood. 92 (7): 2244–51. PMID   9746761.
  30. ↑ Schneider SM, Pritchard SM, Wudiri GA, Trammell CE, Nicola AV (May 2019). Dermody TS (ed.). "Early Steps in Herpes Simplex Virus Infection Blocked by a Proteasome Inhibitor". mBio. 10 (3): e00732–19, /mbio/10/3/mBio.00732–19.atom. doi:10.1128/mBio.00732-19. PMC   6520451 . PMID   31088925.
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