Paraspeckle

In anatomy, a paraspeckle is an irregularly shaped compartment of the cell, approximately 0.2-1 μm in size,[1] found in the nucleus' interchromatin space.[2] First documented in HeLa cells, where there are generally 10-30 per nucleus,[3] paraspeckles are now known to also exist in all human primary cells, transformed cell lines and tissue sections.[4] Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckle" refers to the splicing speckles to which they are always in close proximity.[3] Their function is not known, but they may localize proteins in the nucleus.

Localization

Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent.[2] All five of the proposed protein components have RNA recognition motifs (RRMs)[3] and, in the absence of RNA polymerase II transcription, the paraspeckle disappears and all of its associated proponents form a crescent shaped perinucleolar cap in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present during interphase and during all of mitosis except for telophase because, when the two daughter nuclei are formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap. The localization patterns were also duplicated in experiments using transcription inhibiting drugs.[4]

Function

The function of the paraspeckle nuclear domain, as a whole, is still not well understood. It has been postulated that the activity of p54nrb, a protein component, is dependent on its localization.[4] It is therefore possible that the paraspeckle's role is to provide ordered localization of its component proteins and to thereby help direct their activity. It has also been suggested that the paraspeckle contributes to transcriptional regulation.[5] Neither of these hypotheses, however, is universally accepted and therefore insight into the paraspeckle's larger role must be derived from the function of its protein components (PSP1, p54nrb, PSP2 and possibly CFI(m)68 and PSF).

The function of PSP1, the protein whose localization pattern led to the discovery of the paraspeckle,[2] is not well understood. Myojin et al. speculated that PSP1, which is highly concentrated in the testis, may regulate the germ cells' early mRNA processing and assist in chromatin remodeling and nuclear shaping during spermatogenesis.[6] PSP1 also forms a dimer with the second protein component: p54nrb. P54nrb has reported involvement in numerous nuclear events including "transcriptional regulation, splicing, DNA unwinding, nuclear retention of hyperedited dsRNA, viral RNA processing, control and cell proliferation, and circadian rhythm maintenance".[4] The final confirmed component, PSP2, is involved in RNA splicing and coactivates hormone receptors.[3]

Later studies have led to the identification of two additional proteins that are likely components of the paraspeckle. In 2004 Dettwiler et al. revealed CFI(m)68 as a possible component of the paraspeckle.[7] CFI(m)68 has been implicated with the preliminary step in pre-mRNA 3' end splicing. Fox et al.'s 2005 article also contains evidence of a possible fifth protein component of the paraspeckle: PSF.[4] PSF can bind both RNA and DNA and interacts with pre-mRNA splicing proteins that work in conjunction with proteins like CFI(m)68.[6] It can dimerize with p54nrb. Furthermore, it colocalizes with PSP1 both in the paraspeckle and, if in the presence of transcription inhibiting drugs, in the same perinucleolar cap.[4] If PSF is in fact part of the paraspeckle that would help further substantiate an assertion by Myojin, et al. that paraspeckle components may participate in pre-mRNA splicing.

In 2005 a new role for paraspeckles in a novel method for controlling gene expression was reported by Prasanth et al.[8] In this study, a nuclear enriched non-coding RNA (termed CTNRNA) was identified that specifically localised to paraspeckles in the nuclei of several cell types. The group found that the RNA was retained in the nucleus at paraspeckles, and was associated with the paraspeckle proteins P54nrb and PSP1, likely through direct interactions between the proteins and motifs in the 3' untranslated (3' UTR) region of the RNA. The CTN non-coding RNA is a longer transcript produced from a gene that also encodes the membrane protein MCAT2, a cationic amino acid transporter. When cells became stressed, the nuclear non-coding RNA levels were reduced, coupled with an increase in cytoplasmic signal for the MCAT2 mRNA and protein. This led the authors to speculate that the paraspeckles were effectively a storage site for the spliced and processed CTN RNA, that were able to release the RNA in a functional protein-encoding form when the cell received a signal. This shorter form was then free to be transported to the cytoplasm and used as a template for protein production. This 'Rapid Release Nuclear Retention mechanism' is thought to save the cell 25 minutes in the production of the mCAT2 protein, as the RNA has already been transcribed, processed and spliced whilst it is being held in the paraspeckles.

Future research

Though much about the paraspeckle—including its function—remains unknown, the sub-organelle provides a model of the dynamic nature and of the spatial organization of the nucleus. Better understanding this may lead to therapies for molecular diseases caused by mis-organization of nuclear protein.[2]

References

  1. ↑ Fox, Archa (2007-03-07). "Paraspeckle Size" (Interview). Interview with R. Sundby. E-mail Correspondence.
  2. 1 2 3 4 Fox, A.; et al. (2002). "Paraspeckles: A Novel Nuclear Domain". Current Biology. 12 (1): 13–25. doi:10.1016/S0960-9822(01)00632-7. PMID 11790299.
  3. 1 2 3 4 Fox, Archa; Wendy Bickmore (2004). "Nuclear Compartments: Paraspeckles". Retrieved 6 March 2007.
  4. 1 2 3 4 5 6 Fox, A.; et al. (2005). "P54nrb Forms a Heterodimer with PSP1 That Localizes to Paraspeckles in an RNA-dependent Manner". Molecular Biology of the Cell. 16 (11): 5304–15. doi:10.1091/mbc.E05-06-0587. PMC 1266428Freely accessible. PMID 16148043.
  5. ↑ Schuldt, A. (2002). "Proteomics of the nucleolus". Nature Cell Biology. 4 (2): E35. doi:10.1038/ncb0202-e35. PMID 11835055.
  6. 1 2 Myojin R, Kuwahara S, Yasaki T, et al. (2004). "Expression and Functional Significance of Mouse Paraspeckle Protein 1 on spermatogenesis". Biology of Reproduction. 71 (3): 926–932. doi:10.1095/biolreprod.104.028159. PMID 15140795.
  7. ↑ Dettwiler S, Aringhieri C, Cardinale S, Keller W, Barabino SM (2004). "Distinct sequence motifs within the 68-kDa subunit of cleavage factor Im mediate RNA binding, protein-protein interactions, and subcellular localization". J. Biol. Chem. 279 (34): 35788–97. doi:10.1074/jbc.M403927200. PMID 15169763.
  8. ↑ Prasanth KV, Prasanth SG, Xuan Z, et al. (2005). "Regulating gene expression through RNA nuclear retention". Cell. 123 (2): 249–63. doi:10.1016/j.cell.2005.08.033. PMID 16239143.

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