39 / 2026-03-23 14:20:34

m6A-Dependent Phase Separation of Paraspeckles is critical for Nuclear Export of Stress RNAs spatially associated with NEAT1 locus

Paraspeckles, m6A, 3D-genome, stress response, NEAT1

Paraspeckles are mammalian-specific, membrane-less nuclear organelles formed in most somatic cells with NEAT1 as the architectural RNA.The key role of paraspeckles remains unclear. Here, we found paraspeckles collapse in minutes at 42°C in human cells independent of known heat shock response driver. Exogenous paraspeckle proteins with folding deficits also cause paraspeckle collapse at 37°C. The depletion of the nuclear m⁶A reader YTHDC1 leads to heat-resistant paraspeckles with attenuated liquid-liquid phase separation (LLPS) due to TDP-43 overaccumulation. A single m⁶A site on NEAT1 is critical for LLPS of paraspeckles and cell viability under stress through regulating the isoform switch of NEAT1. Heat-induced paraspeckle collapse promotes the nuclear export of paraspeckle-sequestered RNAs, primarily those encoding heat shock proteins, specifically at the early stage. Our study reveals paraspeckles serve as pre-stress reservoirs for stress RNAs under normal conditions, enabling their rapid nuclear export through immediate collapse triggered by exchanging with unfolded paraspeckle proteins. (Mol Cell, in revision)