Nuclear dots

ND10s in human embryonic lung cells

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.

Nuclear dots (also known as Nuclear bodies, nuclear domains, or PML bodies) are punctate structures found in the nuclei of certain cells. Nuclear bodies (NBs) were first seen as prominent interchromatin structures in the nuclei of malignant or hyperstimulated animal cells^[1][2] 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.^[3] Nuclear dots are metabolically stable and resistant to nuclease digestion and salt extraction.^[4]

Structure

Simple nuclear bodies (types I and II) and the shells of complex NB (types III, IVa and V) consist of a non-chromatinic fibrillar material which is most likely proteinaceous.^[5] 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.^[5] The primary components of the nuclear dots are the proteins sp100 nuclear antigen, LYSP100(a homolog of sp100),^[6] ISG20,^[7] PML antigen, NDP55 and 53kDa protein associated with the nuclear matrix.^[8] Other proteins, such as PIC1/SUMO-1, which are associated with nuclear pore complex also associate with nuclear dots.^[9] The proteins can reorganize in the nucleus, by increasing number of dispersion in response to different stress (stimulation or heat shock, respectively).^[10]

Function

One of the nuclear dot proteins appears to be involved in transcriptional active regions.^[11] 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,^[2] and specifically inhibits the infection of vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus,^[12] 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.^[13] whereas overexpression of PML results in programmed cell death.^[14]

One hypothesized function of the dots is as a 'nuclear dump' or 'storage depot'. ^[15] The nuclear bodies may not all perform the same function. Sp140 associates with certain bodies and appears to be involved in transcriptional activation.^[16]

Pathology

These, or similar, bodies have been found increased in the presence of lymphoid cancers^[17][18] and SLE (lupus).^[19] They are also observed at higher frequencies in subacute sclerosing panencephalitis in these instances antibodies to measles shows expression and localization to the bodies.^[20]

• In Promyelocytic Leukemia (PML) the oncogenic PML-RARalpha chimera disrupts normal concentration of PML into nuclear bodies. Addition of As₂O₃, retenoic acid causes remission of this leukemia by triggering their reorganization. As₂O₃ destroys the chimera, allowing new SUMO-1 ubiquitinated PML to relocalize to nuclear bodies.^[13] Retinoic acid induces a caspase-3 mediated degradation of the same chimera.^[21]
• In HHV, ICP0 disrupts nuclear dots in the early stage of infection.

References

1. Brasch K, Ochs RL (1992). "Nuclear bodies (NBs): a newly "rediscovered" organelle". Exp. Cell Res. 202 (2): 211–23. doi:10.1016/0014-4827(92)90068-J. PMID 1397076.
2. Sternsdorf T, Grötzinger T, Jensen K, Will H (1997). "Nuclear dots: actors on many stages". Immunobiology. 198 (1–3): 307–31. doi:10.1016/s0171-2985(97)80051-4. PMID 9442402.
3. Pawlotsky JM, Andre C, Metreau JM, Beaugrand M, Zafrani ES, Dhumeaux D (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.
4. Ascoli CA, Maul GG (1991). "Identification of a novel nuclear domain". J. Cell Biol. 112 (5): 785–95. doi:10.1083/jcb.112.5.785. PMC 2288866. PMID 1999457.
5. Chaly N, Setterfield G, Kaplan JG, Brown DL (1983). "Nuclear bodies in mouse splenic lymphocytes: II - Cytochemistry and autoradiography during stimulation by concanavalin A". Biol. Cell. 49 (1): 35–43. doi:10.1111/j.1768-322x.1984.tb00220.x. PMID 6199062.
6. Dent AL, Yewdell J, Puvion-Dutilleul F, Koken MH, de The H, Staudt LM (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. PMID 8695863.
7. Gongora C, David G, Pintard L, et al. (1997). "Molecular cloning of a new interferon-induced PML nuclear body-associated protein". J. Biol. Chem. 272 (31): 19457–63. doi:10.1074/jbc.272.31.19457. PMID 9235947.
8. Zuber M, Heyden TS, Lajous-Petter AM (1995). "A human autoantibody recognizing nuclear matrix-associated nuclear protein localized in dot structures". Biol. Cell. 85 (1): 77–86. doi:10.1016/0248-4900(96)89129-5. PMID 8882521.
9. Sternsdorf T, Jensen K, Will H (1997). "Evidence for Covalent Modification of the Nuclear Dot–associated Proteins PML and Sp100 by PIC1/SUMO-1". J. Cell Biol. 139 (7): 1621–34. doi:10.1083/jcb.139.7.1621. PMC 2132645. PMID 9412458.
10. Maul GG, Yu E, Ishov AM, Epstein AL (1995). "Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress". J. Cell. Biochem. 59 (4): 498–513. doi:10.1002/jcb.240590410. PMID 8749719.
11. Xie K, Lambie EJ, Snyder M (1993). "Nuclear dot antigens may specify transcriptional domains in the nucleus". Mol. Cell. Biol. 13 (10): 6170–9. PMC 364676. PMID 8413218.
12. Chelbi-Alix MK, Quignon F, Pelicano L, Koken MH, de Thé H (1998). "Resistance to Virus Infection Conferred by the Interferon-Induced Promyelocytic Leukemia Protein". J. Virol. 72 (2): 1043–51. PMC 124576. PMID 9444998.
13. Müller S, Matunis MJ, Dejean A (1998). "Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus". EMBO J. 17 (1): 61–70. doi:10.1093/emboj/17.1.61. PMC 1170358. PMID 9427741.
14. Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de Thé H (1998). "PML induces a novel caspase-independent death process". Nat. Genet. 20 (3): 259–65. doi:10.1038/3068. PMID 9806544.
15. Maul GG (1998). "Nuclear domain 10, the site of DNA virus transcription and replication". BioEssays. 20 (8): 660–7. doi:10.1002/(SICI)1521-1878(199808)20:8<660::AID-BIES9>3.0.CO;2-M. PMID 9780840.
16. Bloch DB, Chiche JD, Orth D, de la Monte SM, Rosenzweig A, Bloch KD (1999). "Structural and Functional Heterogeneity of Nuclear Bodies". Mol. Cell. Biol. 19 (6): 4423–30. PMC 104401. PMID 10330182.
17. Rivas C, Oliva H (1974). "Nuclear bodies in Hodgkin's disease". Pathologia Europaea. 9 (4): 297–301. PMID 4457783.
18. Tani E, Ametani T (1975). "Nuclear characteristics of malignant lymphoma in the brain". Acta neuropathologica. Supplementum. Suppl 6: 167–71. doi:10.1007/978-3-662-08456-4_28. PMID 168720.
19. Jones JM, Martinez AJ, Joshi VV, McWilliams N (1975). "Systemic lupus erythematosus". Archives of pathology. 99 (3): 152–7. PMID 164172.
20. Brown HR, Thormar H (1976). "Immunoperoxidase staining of simple nuclear bodies in sclerosing panencephalitis (SSPE) by antiserum to Measles nucleocapsids". Acta Neuropathol. 36 (3): 259–67. doi:10.1007/BF00685370. PMID 795259.
21. Nervi C, Ferrara FF, Fanelli M, et al. (1998). "Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein". Blood. 92 (7): 2244–51. PMID 9746761.