Paraspeckle nuclear condensates: Global sensors of cell stress?

Abstract

Paraspeckles are nuclear condensates, or membranelees organelles, that are built on the long noncoding RNA, NEAT1, and have been linked to many diseases. Although originally described as constitutive structures, here, in reviewing this field, we develop the hypothesis that cells increase paraspeckle abundance as part of a general stress response, to aid pro-survival pathways. Paraspeckles increase in many scenarios: when cells transform from one state to another, become infected with viruses and bacteria, begin to degenerate, under inflammation, in aging, and in cancer. Cells increase paraspeckles by increasing transcription of NEAT1 and adjusting its RNA processing.These increases in NEAT1 are driven by numerous stress-sensing signaling pathways, including signaling to mitochondria and stress granules, revealing crosstalk between the cytoplasm and nucleoplasm in the stress response. Thus, paraspeckles are an important piece of the puzzle in cellular homeostasis, and could be considered RNAscaffolded nuclear equivalents of dynamic stress-induced structures that form in the cytoplasm. We speculate that, in general, cells rely on phase-separated paraspeckles to transiently tweak gene regulation in times of cellular flux.

Long Noncoding RNAs as Emerging Regulators of COVID-19

“…However, recent studies found that MALAT1 can reduce the epigenetic silencing of viral transcription by regulating promoter-enhancer interactions to promote viral transcription and infection ( 39 ). In addition, other studies have shown that lncRNA NEAT1 controls RNA regulatory processes by forming nonmembranous organelle nuclear paraspeckles ( 40 ). Knockout of NEAT1 can enhance viral production by promoting the export of HIV-1 mRNA from the nucleus to the cytoplasm in HeLa cells ( 41 ).…”

Tumour mutations in long noncoding RNAs enhance cell fitness

“…NEAT1_1 is a ubiquitous, abundant, polyadenylated and highly conserved transcript (Nakagawa et al, 2011). In contrast, NEAT1_2, responsible for formation of membraneless nuclear paraspeckle structures, is not polyadenylated and expressed under specific conditions or in response to various forms of stress (Adriaens et al, 2019; McCluggage and Fox, 2021).…”

“…NEAT1 is a necessary component of subnuclear paraspeckles (Fox et al, 2002; Hutchinson et al, 2007; McCluggage and Fox, 2021), which assemble when specific architectural proteins bind to nascent NEAT1_2 transcripts (Mao et al, 2011). Paraspeckles are nuclear condensates containing diverse gene regulatory proteins (McCluggage and Fox, 2021). They are often observed in cancer cells, (Adriaens et al, 2016), and are associated with poor prognosis (Li et al, 2018a).…”

“…Additionally, the resulting lists of proteins were filtered for nuclear localization (Uhlen et al, 2015) to exclude potential false positives. To calculate the significance of the overlap with known NEAT1 binding proteins (Huang et al, 2020; Spiniello et al, 2018; West et al, 2014) and known paraspeckle proteins (McCluggage and Fox, 2021) a hypergeometric test was applied to the background of all nuclear proteins (n=6758). STRING was used for interaction analysis (physical subnetwork, minimum interaction score=0.4, max number of direct interactors=10) and GO term enrichment analysis (Szklarczyk et al, 2019).…”

LncRNA NEAT1 Recruits SFPQ to Regulate MITF Splicing and Control RPE Cell Proliferation

“… 33 Paraspeckles are nuclear condensates that increase with changes in the state of cells, including responses to stress. 52 Mature RPE cells are believed to remain in a non-proliferative state throughout life, but in specific disease conditions, such as retinal detachment or PVR, the RPE cells undergo EMT and start to proliferate. It is still unclear whether paraspeckles regulate the cell-cycle state change in RPE cells, but our findings suggest that paraspeckle-related proteins or RNAs might be potential mechanisms through which RPE cell proliferation might be regulated.…”