Paraspeckle

Physiological

The main insight into their physiological function is their location. Prominent Paraspeckles are only found in a subpopulation of cells in murine tissues, e.g. luteal cells or cells at the tip of the gut epithelium.^[9] Hence, based on location Paraspeckles are thought to play a role in cancer regulation, reproduction and viral management.

One focus has been the Paraspeckle's role in cancer and cell stress scenarios. Wang, Z, Li K, Huang, W (2019),^[11] records that quantities of NEAT1 and thus Paraspeckles are increased in digestive system tumours and respiratory cancers. Furthermore, that expression of NEAT1 is associated with tumour size, stage of cancer, ability to spread and overall patient survival. Whilst, failure to regulate NEAT1 production has been linked to non-cancerous diseases, such as neurodegenerative diseases like Parkinson's or Alzheimer's.^[11] However, the function of NEAT1 and Paraspeckles is not always positive, it has been proven that they enhance the malignancy and stemness of breast tumours by increasing the expression of the WNT4 gene.^[4]

NEAT1 also affects pregnancy and fertility chances, especially in female mammals whose luteal cells are regulated by Paraspeckles.^[10] This can cause malformation or potential no formation of the corpus luteum leading to infertility, smaller litters, and fewer viable pregnancies. In a study by Chai Y, Liu J, Zhang Z, Liu L (2016),^[9] knockout mice (no NEAT1) exhibited malfunctions in epithelial cell proliferation, causing mothers to lactate poorly and reduced litter survival even further. Interestingly these knockout mice exhibit the stochastic effect; the corpus luteum will form in some, but not in all.^[9] This reinforces the fact that Paraspeckles are inducible by cell stress and that environmental triggers have an impact.

From a viral aspect, NEAT1 levels have an observable impact on infections within cells with many different RNA viruses, including Japanese encephalitis, rabies,^[11] HIV,^[11][12] influenza,^[13] and Hantaan,^[14] as well as the DNA-encoded herpes simplex virus.^[15] Wang, Z, Li K, Huang, W (2019)^[11] suggest NEAT1_2/Paraspeckles act as a promoter to cell defence triggering and aiding the cellular defence mechanism.

Molecular

From the molecular perspective, this page examines the Paraspeckle's function through NEAT1, NONO (p45nrb) and SFPQ (PSF).

One aspect of the Molecular function is the Paraspeckle's ability to sequester other molecules affecting transcription. This is done by both NEAT1 and some constituent proteins. NEAT1 is primarily responsible for the Paraspeckle's architecture and providing stability to the protein components.^[11] Yet, it has also been shown to regulate gene expression. This is done by recruiting transcription factors, sequestering them from gene promoters and ultimately altering transcription.^[5][16][17] Furthermore, Wang, Z, Li K, Huang, W (2019)^[11] state that NEAT1 can regulate expression by associating with RNA-binding proteins this regulates RNA splicing events and can manipulate the stability of proteins. Another form of molecule sequestering is through NONO and SFPQ, both proteins can bind to double-stranded RNA that has formed as a result of transcribed inverted repeat motifs.^[9]

Another aspect of molecular function is NEAT1's localisation of Paraspeckle proteins to direct their activity. In a study by Hirose, T. et al. (2014),^[6] when NEAT1_2 levels increase, Paraspeckles elongate. This, in turn, not only increases Paraspeckle length but also the demand for more Paraspeckle proteins to build the tertiary structures required for proper functioning. This reduces nucleoplasmic protein availability. It was noted in their study that this has an impact on the role of free Paraspeckle proteins such as SFPQ which normally represses IL-8, an immune-responsive gene, or can activate the ADARB2 gene. Thus, gene regulation can be manipulated not just through sequestering of non-constituent proteins but also Paraspeckle constitutive proteins.