FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1081912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28155750_1.fastq.gz | Fastqsanger.gz | |||
| SRR28155750_2.fastq.gz | Fastqsanger.gz | |||
| SRR28155751_1.fastq.gz | Fastqsanger.gz | |||
| SRR28155751_2.fastq.gz | Fastqsanger.gz | |||
| SRR28155752_1.fastq.gz | Fastqsanger.gz |
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Project description:FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here we identify that FOXK2 is sensitive to degradation by the virulent pathogens P. aeruginosa and K. pneumoniae in lung epithelia through ubiquitin-proteasomal processing. FOXK2 through its carboxyl-terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxyl-terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to wild-type littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.
2024-05-10 | GSE260512 | GEO
Project description:FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here we identify that FOXK2 is sensitive to degradation by the virulent pathogens P. aeruginosa and K. pneumoniae in lung epithelia through ubiquitin-proteasomal processing. FOXK2 through its carboxyl-terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxyl-terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to wild-type littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.
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Project description:The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyper-activation of the mTOR pathway in human cancers, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based high-throughput chemical genetic screen to identify small-molecule enhancers of rapamycin (SMERs) and used whole genome expression analysis to identify their mechanisms of action. This SuperSeries is composed of the following subset Series: GSE22270: Expression data from Saccharomyces cerevisiae Met30 temperature-sensitive strain GSE22271: Expression data from Saccharomyces cerevisiae temperature-sensitive strains specific for SCF core components (Skp1, Cullin (Cdc53), E2 enzyme (Cdc34)) and the F-box protein Cdc4. Refer to individual Series
2011-06-30 | E-GEOD-22272 | biostudies-arrayexpress
Project description:Selective protein degradation typically involves substrate recognition via short linear motifs known as degrons. Various degrons can be found at protein termini from bacteria to mammals. While N-degrons have been extensively studied, our understanding of C-degrons is still limited. Towards a comprehensive understanding of eukaryotic C-degron pathways, we performed an unbiased survey of C-degrons in budding yeast. We identified over 5000 potential C-degrons by stability profiling of random peptide libraries and of the yeast C-terminome. Combining machine learning, high-throughput mutagenesis and genetic screens revealed that the SCF ubiquitin ligase targets ~40% of degrons using a single F-box substrate receptor Das1. Although sequence-specific, Das1 is highly promiscuous, recognizing a variety of C-degron motifs. By screening for full-length substrates, we implicate SCFDas1 in degradation of orphan protein complex subunits. Altogether, this work highlights the variety of C-degron pathways in eukaryotes and uncovers how an SCF/C-degron pathway of broad specificity contributes to proteostasis.
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Project description:Cells adapt to ever-changing environmental cues by remodeling their inventories of multiprotein complexes. The cellular repertoire of modular multiprotein SCF (SKP1-CUL1-Fbox protein) E3 ligase complexes - which mediate much protein degradation - requires CAND1 to distribute the limiting CUL1 subunit as needed across the family of ~70 different Fbox proteins. Yet how a single assembly factor coordinately promotes dissociation of idling complexes and formation of numerous distinct multiprotein complexes as needed remains unknown. Here, we address this by obtaining cryo-EM structures of CAND1-bound SCF complexes in multiple states, and correlating effects of mutations on the conformational ensembles and in biochemical and cellular assays. The data suggest CAND1 initially clasps catalytic domains of an inactive SCF, rolls around, and allosterically rocks and destabilizes the SCF interface. New SCF production proceeds in reverse, through SKP1 and the Fbox allosterically reducing interactions with CAND1. The CAND1-SCF conformational ensemble fuels mixing-and-matching of SCF parts in response to substrate availability. Thus, our data reveal the biogenesis of a predominant family of E3 ubiquitin ligases, and the molecular basis for systemwide multiprotein complex assembly.
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Project description:Neuronal development requires proper migration, polarization and establishment of axons and dendrites. Growing evidence identifies the ubiquitin proteasome system (UPS) with its numerous components as an important regulator of various aspects of neuronal development. F-box proteins are interchangeable subunits of the Cullin-1 based E3 ubiquitin ligase, but only a few family members have been studied. Here, we report that the centrosomal E3 ligase FBXO31-SCF (Skp1/Cullin-1/F-box protein) regulates neuronal morphogenesis and axonal identity. In addition, we identified the polarity protein Par6c as a novel interaction partner and substrate targeted for proteasomal degradation in the control of axon but not dendrite growth. Finally, we ascribe a role for FBXO31 in dendrite growth and neuronal migration in the developing cerebellar cortex. Taken together, we uncovered the centrosomal E3 ligase FBXO31-SCF as a novel regulator of neuronal development.
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2011-06-30 | GSE22272 | GEO
Project description:RAW files, mzML files, search results (gpm.xml), TPP analysis files (pep.XML and prot.XML, as well as tab delimited output of pep.XML as .xls) and analyzed results Table 1 for the identification of BTRCP1/2 substrates using BioID. The identification of ubiquitin E3 ligase substrates has been extremely challenging, due in part to low-affinity, transient interactions, the rapid degradation of targets, and the inability to identify proteins from poorly soluble cellular compartments. SCF-TrCP1 and SCF-TrCP2 are well studied ubiquitin E3 ligases that target substrates for proteasomal degradation, and play important roles in Wnt, Hippo and NFB signalling. Combining 26S proteasome inhibitor (MG132) treatment with proximity-dependent biotin labeling (BioID) and semi-quantitative mass spectrometry, here we identify SCF-TrCP1/2 interacting partners. Based on their enrichment in the presence of MG132, our data identify over 50 new putative SCF-TrCP1/2 substrates. We validate 12 of these new substrates, and reveal previously unsuspected roles for -TrCP in the maintenance of nuclear membrane integrity, processing (P)-body turnover, and translational control. Together, our data suggest that -TrCP is an important hub in the cellular stress response. The approach presented here should be broadly applicable for the identification of substrates for many ubiquitin E3 ligases.
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