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Collective homeostasis of condensation-prone proteins via their mRNAs

ABSTRACT: The concentration of proteins containing intrinsically disordered regions must be tightly controlled to maintain cellular homeostasis. However, mechanisms for collective control of these proteins, which tend to localise to membraneless condensates, are less understood compared to pathways mediated by membrane-bound organelles. Here we report ‘interstasis’, a homeostatic mechanism in which increased concentration of proteins within RNA-protein condensates induces the sequestration of their own mRNAs. The selectivity of interstatic mRNA capture relies on the structure of the genetic code and conserved codon biases, which ensure that similar multivalent RNA regions encode similar low-complexity domains. For example, arginine-enriched mixed charge domains (R-MCDs) tend to be encoded by repetitive purine-rich sequences in mRNAs. Accumulation of proteins containing R-MCDs increases the cohesion of nuclear speckles, which induces selective capture of purine-rich multivalent mRNAs. The multivalent regions are bound by specific RNA-binding proteins, including TRA2 proteins, which relocalise to speckles upon interstasis to promote selective mRNA capture. CLK-mediated phosphorylation of TRA2 proteins counters their localisation to speckles, thereby modulating interstasis. Thus, the condensation properties of nuclear speckles act as a sensor for interstasis, a collective negative-feedback loop that co-regulates mRNAs of many highly dosage-sensitive genes, which primarily encode nuclear phase-separation prone proteins. Using pulsed Stable Isotope Labelling by Amino acids in Cell culture (pSILAC), we demonstrate that the selective nuclear retention of purine-rich mRNA transcripts upon R-MCD accumulation corresponds with the downregulated translation of the proteins these mRNAs encode.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Steven Lynham

LAB HEAD: Jurnej Ule

PROVIDER: PXD066402 | Pride | 2025-07-30

REPOSITORIES: Pride

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			Action	DRS
	PR832_Neve_20250415_T10_20250417140256.msf	Msf
	PR832_Neve_20250415_T10_20250417140256.mzTab	Mztab
	PR832_Neve_20250415_T10_20250417140256.raw	Raw
	PR832_Neve_20250415_T11_20250417180804.msf	Msf
	PR832_Neve_20250415_T11_20250417180804.mzTab	Mztab

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Project description:Nuclear speckles are dynamic nuclear bodies characterized by high local concentrations of RNA binding proteins and specific non-coding RNAs. Although the contents of speckles suggest multifaceted roles in regulating chromatin dynamics and gene expression, the overarching biological function(s) of nuclear speckles remain enigmatic. In this study, we investigate speckle compositional variation in human cancer, finding two main speckle compositional states based on RNA expression of speckle-resident proteins. One cancer speckle state was more similar to normal adjacent tissues, while the other was dissimilar from normal tissue, and thus considered an aberrant cancer speckle state. We link the aberrant speckle state to altered speckle positioning within the nucleus, to elevation of the TREX RNA export complex, and to worse patient outcomes in clear cell renal cell carcinoma (ccRCC). ccRCC is typified by hyperactivation of the HIF-2a transcription factor, and we demonstrate that HIF-2a drives physical association of a select subset of its target genes with nuclear speckles depending on HIF-2a's two speckle targeting motifs (STMs) defined in this study. STMs are highly enriched among transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation and providing a resource of candidate speckle-targeting factors. Via integration of tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2a gene regulatory programs are impacted by speckle compositional state and by abrogation of speckle targeting abilities of HIF-2a. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2a-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumor speckle compositional states broadly correlate with altered functional pathways and expression of speckle-associated gene neighborhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.

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Collective homeostasis of condensation-prone proteins via their mRNAs

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