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SRSF1 sustains the nucleolus by charge-modulated pH regulation

ABSTRACT: Nucleolus is a multiphase biomolecular assembly containing three distinct subcompartments. Evidence is just emerging that nucleolar proteins with characteristic electrochemical properties condense to generate a pH gradient, which serves as a key driving force for organizing the nucleolar sub-phases. Given the indispensable functionality of the nucleolus in most, if not all, cellular activities, it is vital for a cell to sense potential fluctuations in the nucleolar pH and subsequently maintain pH homeostasis. The mechanisms by which a cell achieves this task remain poorly decoded. Here, we show that splicing factor SRSF1 is shuttled from nuclear speckle (NS) to the nucleolus during times of stress, which interrogates the nucleolar pH. SRSF1 nucleolar localization is reliant on an acidic patch. Loss of SRSF1 impedes pH homeostasis in the dark nucleolar cap and subsequently obstructs the restoration of the nucleolar multiphase and function. The RS (arginine/serine rich) domain of SRSF1, due to its high isoelectric point (pI), directly alkalinizes the nucleolar microenvironment. Interestingly, synthetic arginine-rich dipeptide derivatives of SRSF1 RS domain safeguard the nucleolus from pH and functional disturbance. Our findings uncover unprecedented mechanistic insights into nucleolar pH-sensing and regulation.

ORGANISM(S): Homo Sapiens

SUBMITTER: Bo Wang

PROVIDER: PXD073906 | iProX | Sat Jan 31 00:00:00 GMT 2026

REPOSITORIES: iProX

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SRSF1 modulates the pH microenvironment of the dark nucleolar caps to restorenucleolar integrity and function

Project description:Nucleolus is a multiphase biomolecular assembly containing three distinct subcompartments. Evidence is just emerging that nucleolar proteins with characteristic electrochemical properties condense to generate a pH gradient, which serves as a key driving force for organizing the nucleolar sub-phases. Given the indispensable functionality of the nucleolus in most, if not all, cellular activities, it is vital for a cell to sense potential fluctuations in the nucleolar pH and subsequently maintain pH homeostasis. The mechanisms by which a cell achieves this task remain poorly decoded. Here, we show that splicing factor SRSF1 is shuttled from nuclear speckle (NS) to the nucleolus during times of stress, which interrogates the nucleolar pH. SRSF1 nucleolar localization is reliant on an acidic patch. Loss of SRSF1 impedes pH homeostasis in the dark nucleolar cap and subsequently obstructs the restoration of the nucleolar multiphase and function. The RS (arginine/serine rich) domain of SRSF1, due to its high isoelectric point (pI), directly alkalizes the nucleolar microenvironment. Interestingly, synthetic arginine-rich dipeptide derivatives of SRSF1 RS domain safeguard the nucleolus from pH and functional disturbance. Our findings uncover unprecedented mechanistic insights into nucleolar pH-sensing and regulation.

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Precise genomic editing of a pathogenic RBM20 mutation rescues dilated cardiomyopathy

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The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function [ChIP-Seq]

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The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function [RNA-Seq]

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The master energy homeostasis regulator PGC-1α couples transcriptional co-activation and mRNA nuclear export

Project description:PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1α-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing and neurodegenerative diseases.

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RNA-Seq of 293T cells depleted of U2AF-related proteins

Project description:Characterization of RNA processing events dependent on U2AF-related proteins PUF60 and RBM39. PUF60 (poly-U-binding factor 60 kDa, also known as FIR, Hfp or Ro-bp1) is a splicing factor homologous to the 65 kD subunit of the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF65). PUF60 has two central RNA recognition motifs and a C-terminal U2AF homology motif (UHM), but lacks the N terminal arginine/serine-rich (RS) and UHM ligand motif (ULM) domains present in U2AF65. PUF60 activity, in conjunction with U2AF, facilitates the association of U2 snRNP with the pre-mRNA. PUF60 and U2AF65 can bind SF3b155 ULMs simultaneously and noncompetitively. RBM39 (also known as CAPERα, HCC1, FSAP59 or RNPC2) is an RNA processing factor and a hormone-dependent transcriptional coactivator. RBM39 domain structure is similar to PUF60, except for the extra N-terminal RS domain with unknown function. To understand function of the two proteins on a genome-wide scale, each protein was individually depleted from human embryonic kidney cell line 293 using RNAi to systematically characterize the PUF60- and RBM39-dependent exon usage.

2018-05-25 | E-MTAB-6010 | biostudies-arrayexpress

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2023-06-19 | PXD038790 | Pride

A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress

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