PXD066402-1

PXD066402 is an original dataset announced via ProteomeXchange.

Title	Collective homeostasis of condensation-prone proteins via their mRNAs
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-07-30
AnnouncementXML	Submission_2025-07-30_05:19:21.935.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD066402
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Steven Lynham
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-22 01:50:44	ID requested
⏵ 1	2025-07-30 05:19:22	announced

10.6019/PXD066402;

submitter keyword: HeLa, pSILAC, mScarlet, LCD, interstasis, Human, PPIG, IDR, nuclear speckle, condensate, multivalency, LC-MS/MS

Jurnej Ule
contact affiliation	The Francis Crick Institute, London UK Dementia Research Institute at King's College London, UK National Institute of Chemistry, Ljubljana, Slovenia
contact email	jurnej.ule@kcl.ac.uk
lab head
Steven Lynham
contact affiliation	King's College London
contact email	steven.lynham@kcl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066402
     1. Label: PRIDE project
     2. Name: Collective homeostasis of condensation-prone proteins via their mRNAs