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Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set2: PIM1 AP-MS

ABSTRACT: Mitochondria consist of hundreds of proteins, most of which are long-lived and inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions is poorly understood. Here we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Thereby different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 associates with a different type of intramitochondrial aggregate. These Hsp78-bound aggregates sequester non-native matrix proteins to promote their subsequent folding or Pim1-mediated degradation. Our study shows that mitochondrial proteins actively control the formation of different types of intramitochondrial protein aggregates which actively cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Cell Culture

SUBMITTER: Markus Räschle

LAB HEAD: Markus Räschle

PROVIDER: PXD045286 | Pride | 2024-03-26

REPOSITORIES: Pride

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Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set3: VAR1 AP-MS

Project description:Mitochondria consist of hundreds of proteins, most of which are long-lived and inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions is poorly understood. Here we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Thereby different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 associates with a different type of intramitochondrial aggregate. These Hsp78-bound aggregates sequester non-native matrix proteins to promote their subsequent folding or Pim1-mediated degradation. Our study shows that mitochondrial proteins actively control the formation of different types of intramitochondrial protein aggregates which actively cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

2024-03-26 | PXD045288 | Pride

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set1: HSP78 AP-MS

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TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing

Project description:TFIID is an essential eukaryotic transcription factor, which is required for RNA polymerase II promoter recognition and activation. As a multiprotein complex, TFIID contains several intrinsically disordered regions (IDRs), but the functions of these IDRs are unknown. Here, we show that a conserved IDR drives the TFIID subunit TAF2 to nuclear speckles, where it forms biomolecular condensates, separate from the TFIID complex. Quantitative mass spectrometry analyses reveal that the TAF2 IDR is required for the interaction with the nuclear speckle and spliceosome-associated protein SRRM2, which is thereby recruited to TFIID. The formation of SRRM2-free TFIID complexes elicits a set of unique alternative splicing events. These include events in RNAs coding for proteins involved in transcription and transmembrane transport. Together, these data identify an IDR of the basal transcription machinery as a molecular switch between nuclear compartments to control protein complex composition and pre-mRNA splicing.

2024-04-26 | PXD049117 | Pride

Quantitative Proteomics Identify a Novel DNA Repair-Dependent Role for Hepatocyte Nuclear Factor 4α

Project description:Hepatocyte nuclear factor 4 (HNF4) is a transcription factor that acts as a master regulator of genes in several endodermal-derived tissues, including the intestine in which it plays a central role during development and tumorigenesis. To better delineate the mechanisms by which HNF4 can interfere during these processes, we combined stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics with immunoprecipitation of green fluorescent protein (GFP) as well as with proximity-dependent purification by the biotin ligase BirA, both fused to HNF4. Surprisingly, these analyses identified a significant enrichment of proteins falling into the DNA repair gene ontology term, a so far unidentified biological feature of this transcription factor. Several of these proteins including PARP1, RAD50 and DNA-PKcs were confirmed to interact with HNF4in colorectal cancer cell lines. During DNA damage response, HNF4 localized to double strand DNA breaks in these cells. HNF4was able to interfere functionally during non-homologous end-joining (NHEJ). Overall, these observations identify an unsuspected role for this transcription factor during the DNA damage response.

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Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.

2024-01-28 | PXD041254 | Pride

Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

2022-10-14 | PXD031928 | Pride

Dissociated avian utricle sensory epithelia treated with one of various siRNAs or small molecule inhibitors

Project description:The inner ear utilizes sensory hair cells as mechano-electric transducers for sensing sound and balance. In mammals, these sensory hair cells lack the capacity for regeneration and if damaged lead to hearing or balance disorders. However, non-mammalian vertebrates such as birds maintain their regenerative abilities throughout their life. In a previous study we conducted a gene expression profiling time course of regenerating sensory epithelia (SE) in avian cochlea and utricle on a custom transcription factor microarray following damage by both laser and chemical ablation. We identified several known signaling cascades such as The Pax-Eya-Six-Dach pathway, Ap-1 pathway, the Tgf-β pathway and sonic hedgehog signaling that are differentially expressed during SE regeneration. In this study we selected 27 of these genes for knockdown by siRNA or small molecule inhibition to determine their requirement for SE regeneration and identify downstream targets. We assessed phenotypes using a 96 well proliferation assay and expression profiled each knockdown on a custom transcription factor microarray. Using these techniques we have determined several genes that are required for SE proliferation and identified novel epistatic relationships between many of these genes. Pure sensory epithelia was isolated from avian utricles. Sensory epithelia was physically dissociated and grown in 96 well cultures for 3 days. Prior to confluency, dissociated sensory epithelia were transfected with siRNAs (12 pmol/well) or small molecule inhibitor in 0.1% DMSO. RNA was isolated 24 hrs post transfection and assayed on a custom oligonucleotide transcription factor microarray compared to controls (GFP siRNA or 0.1% DMSO only). siRNA: CEBPG, JunD, BTAF1, LRP5, PAX2, PAX5, PAX7, Wnt4, BCL11A, CBX3, CBX4, CTNNB1, CUTL1, MYT1L, RARA, TIMELESS, TRIP15, PAX3, EZH2, HES1, ID1, CDKN1B, and PPARGC1 small molecule inhibition: IGF, MAPK, SHH, and JNK

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