Nuclear bodies explained

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]

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

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

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 insubacute sclerosing panencephalitis

in this instance, antibodies to measles show expression in and localization to the nuclear bodies.[28]

Notes and References

  1. Weber SC . Sequence-encoded material properties dictate the structure and function of nuclear bodies . Current Opinion in Cell Biology . 46 . 62–71 . June 2017 . 28343140 . 10.1016/j.ceb.2017.03.003 .
  2. Zimber A, Nguyen QD, Gespach C . Nuclear bodies and compartments: functional roles and cellular signalling in health and disease . Cellular Signalling . 16 . 10 . 1085–104 . October 2004 . 15240004 . 10.1016/j.cellsig.2004.03.020 .
  3. Rivera-Molina YA, Martínez FP, Tang Q . Nuclear domain 10 of the viral aspect . World Journal of Virology . 2 . 3 . 110–22 . August 2013 . 24255882 . 3832855 . 10.5501/wjv.v2.i3.110 . free .
  4. Lafarga M, Berciano MT, Pena E, Mayo I, Castaño JG, Bohmann D, Rodrigues JP, Tavanez JP, Carmo-Fonseca M . 6 . 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 . August 2002 . 12181345 . 117941 . 10.1091/mbc.e02-03-0122 .
  5. Banani SF, Lee HO, Hyman AA, Rosen MK . Biomolecular condensates: organizers of cellular biochemistry . Nature Reviews. Molecular Cell Biology . 18 . 5 . 285–298 . May 2017 . 28225081 . 7434221 . 10.1038/nrm.2017.7 . 37694361 .
  6. Bhat P, Hanson D, Guttman M . Nuclear compartmentalization as a mechanism for quantitative control of gene expression . Nature Reviews. Molecular Cell Biology . 22 . 5 . 653–670 . August 2021 . 34341548 . 10.1038/s41580-021-00387-1 .
  7. Brasch K, Ochs RL . Nuclear bodies (NBs): a newly "rediscovered" organelle . Experimental Cell Research . 202 . 2 . 211–23 . October 1992 . 1397076 . 10.1016/0014-4827(92)90068-J .
  8. Sternsdorf T, Grötzinger T, Jensen K, Will H . Nuclear dots: actors on many stages . Immunobiology . 198 . 1–3 . 307–31 . December 1997 . 9442402 . 10.1016/s0171-2985(97)80051-4 .
  9. Pawlotsky JM, Andre C, Metreau JM, Beaugrand M, Zafrani ES, Dhumeaux D . Multiple nuclear dots antinuclear antibodies are not specific for primary biliary cirrhosis . Hepatology . 16 . 1 . 127–31 . July 1992 . 1319948 . 10.1002/hep.1840160121 . 22729443 .
  10. Ascoli CA, Maul GG . Identification of a novel nuclear domain . The Journal of Cell Biology . 112 . 5 . 785–95 . March 1991 . 1999457 . 2288866 . 10.1083/jcb.112.5.785 .
  11. Chaly N, Setterfield G, Kaplan JG, Brown DL . Nuclear bodies in mouse splenic lymphocytes: II - Cytochemistry and autoradiography during stimulation by concanavalin A . Biology of the Cell . 49 . 1 . 35–43 . 1983 . 6199062 . 10.1111/j.1768-322x.1984.tb00220.x . 43084163 .
  12. Dent AL, Yewdell J, Puvion-Dutilleul F, Koken MH, de The H, Staudt LM . 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 . August 1996 . 8695863 . 10.1182/blood.V88.4.1423.bloodjournal8841423. free .
  13. Gongora C, David G, Pintard L, Tissot C, Hua TD, Dejean A, Mechti N . Molecular cloning of a new interferon-induced PML nuclear body-associated protein . The Journal of Biological Chemistry . 272 . 31 . 19457–63 . August 1997 . 9235947 . 10.1074/jbc.272.31.19457 . free .
  14. Zuber M, Heyden TS, Lajous-Petter AM . A human autoantibody recognizing nuclear matrix-associated nuclear protein localized in dot structures . Biology of the Cell . 85 . 1 . 77–86 . 1995 . 8882521 . 10.1111/j.1768-322X.1995.tb00944.x .
  15. Sternsdorf T, Jensen K, Will H . 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 . December 1997 . 9412458 . 2132645 . 10.1083/jcb.139.7.1621 .
  16. Maul GG, Yu E, Ishov AM, Epstein AL . 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 . December 1995 . 8749719 . 10.1002/jcb.240590410 . 22209911 .
  17. Xie K, Lambie EJ, Snyder M . Nuclear dot antigens may specify transcriptional domains in the nucleus . Molecular and Cellular Biology . 13 . 10 . 6170–9 . October 1993 . 8413218 . 364676 . 10.1128/MCB.13.10.6170 .
  18. Chelbi-Alix MK, Quignon F, Pelicano L, Koken MH, de Thé H . Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein . Journal of Virology . 72 . 2 . 1043–51 . February 1998 . 9444998 . 124576 . 10.1128/JVI.72.2.1043-1051.1998.
  19. Müller S, Matunis MJ, Dejean A . Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus . The EMBO Journal . 17 . 1 . 61–70 . January 1998 . 9427741 . 1170358 . 10.1093/emboj/17.1.61 .
  20. Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de Thé H . PML induces a novel caspase-independent death process . Nature Genetics . 20 . 3 . 259–65 . November 1998 . 9806544 . 10.1038/3068 . 856232 .
  21. Maul GG . Nuclear domain 10, the site of DNA virus transcription and replication . BioEssays . 20 . 8 . 660–7 . August 1998 . 9780840 . 10.1002/(SICI)1521-1878(199808)20:8<660::AID-BIES9>3.0.CO;2-M . 46499841 .
  22. Bloch DB, Chiche JD, Orth D, de la Monte SM, Rosenzweig A, Bloch KD . Structural and functional heterogeneity of nuclear bodies . Molecular and Cellular Biology . 19 . 6 . 4423–30 . June 1999 . 10330182 . 104401 . 10.1128/MCB.19.6.4423 .
  23. Gu H, Zheng Y . Role of ND10 nuclear bodies in the chromatin repression of HSV-1 . Virology Journal . 13 . 62 . April 2016 . 27048561 . 4822283 . 10.1186/s12985-016-0516-4 . free .
  24. Bhat P, Chow A, Emert B et al . Genome organization around nuclear speckles drives mRNA splicing efficiency. . Nature . 629 . 5 . 1165–1173 . May 2024 . 38720076 . 11164319 . 10.1038/s41586-024-07429-6 .
  25. Rivas C, Oliva H . Nuclear bodies in Hodgkin's disease . Pathologia Europaea . 9 . 4 . 297–301 . 1974 . 4457783 .
  26. Book: Tani E, Ametani T . Nuclear Characteristics of Malignant Lymphoma in the Brain . Malignant Lymphomas of the Nervous System . Acta Neuropathologica. Supplementum . Suppl 6 . 167–71 . 1975 . 168720 . 10.1007/978-3-662-08456-4_28. 978-3-540-07208-9 .
  27. Jones JM, Martinez AJ, Joshi VV, McWilliams N . Systemic lupus erythematosus . Archives of Pathology . 99 . 3 . 152–7 . March 1975 . 164172 .
  28. Brown HR, Thormar H . Immunoperoxidase staining of simple nuclear bodies in sclerosing panencephalitis (SSPE) by antiserum to Measles nucleocapsids . Acta Neuropathologica . 36 . 3 . 259–67 . November 1976 . 795259 . 10.1007/BF00685370 . 38057985 .
  29. Nervi C, Ferrara FF, Fanelli M, Rippo MR, Tomassini B, Ferrucci PF, Ruthardt M, Gelmetti V, Gambacorti-Passerini C, Diverio D, Grignani F, Pelicci PG, Testi R . 6 . Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein . Blood . 92 . 7 . 2244–51 . October 1998 . 9746761 .
  30. Schneider SM, Pritchard SM, Wudiri GA, Trammell CE, Nicola AV . Early Steps in Herpes Simplex Virus Infection Blocked by a Proteasome Inhibitor . mBio . 10 . 3 . e00732–19, /mbio/10/3/mBio.00732–19.atom . May 2019 . 31088925 . 6520451 . 10.1128/mBio.00732-19 . Terence S. . Dermody .

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