Phosphoproteomic analysis of UBQLN2 mutant cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood Serum, Lymphocyte
DISEASE(S): Amyotrophic Lateral Sclerosis
SUBMITTER: 
Joern Dengjel
LAB HEAD: Joern Dengjel
PROVIDER: PXD029730 | Pride | 2022-06-28
REPOSITORIES: Pride
Dataset's files
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| 20210424_MS_male1_P_01_20210430171826.raw | Raw | |||
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| 20210424_MS_male1_P_05.raw | Raw |
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Project description:Protein homeostasis and lipid metabolism are crucial cellular processes that are dysregulated in neurodegeneration. However, their connection in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unexplored. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to familial ALS/FTD and broader neurodegeneration. Here, we idetified UBQLN2 as an essential regulator for intracellular lipid metabolism, the biological processes of which are impaired by ALS/FTD-linked mutations in UBQLN2. Using transcriptome analysis, we profiled the molecular changes in motor neurons derived from isogenic control and UBQLN2-mutant iPSCs under ALS/FTD-associated metabolic stress, glucose deficiency. We found that biological processes related to cell survival and metabolism were greately affected by the disease-linked mutations in UBQLN2, suggesting that the impaired metabolic role of UBQLN2 by the disease-linked mutations is involved in the pathogenesis of relative neurodegeneration.
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Project description:To address whether expression of ALS/FTD-associated UBQLN2 mutant variants changes the cellular proteome, we performed label-free quantification-based global protein abundance profiling of patient-derived LCLs and CRISPR engineered HeLa cells. UBQLN2 mutant in both cell lines carried the mutation T487I or P497S both of which were reported to cause ALS (Deng et al., 2011; Williams et al, 2012). In addition, HeLa cells stably expressing HA-tagged MAP1B (HA-MAP1B) were subjected to HA immunoprecipitation (IP) followed by mass spectrometry to identify MAP1B interacting proteins.
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Project description:Using immunoprecipitations from HEK293T cells of UBQLN2-HA constructs, sites of ubiquitination were identified. A variety of UBQLN2 variants were studied including lysineless proteins, deletions of the UBL domain and N-terminal fusions to ubiquitin.
2025-12-17 | PXD059465 | Pride
Project description:Genetic variants that impact gene regulation are important contributors to human phenotypic variation. For this reason, considerable efforts have been made to identify genetic associations with differences in mRNA levels of nearby genes, namely, cis expression quantitative trait loci (eQTLs). The phenotypic consequences of eQTLs are presumably due, in most cases, to their ultimate effects on protein expression levels. Yet, only few studies have quantified the impact of genetic variation on proteins levels directly. It remains unclear how faithfully eQTLs are reflected at the protein level, and whether there is a significant layer of cis regulatory variation acting primarily on translation or steady state protein levels. To address these questions, we measured ribosome occupancy by high-throughput sequencing, and relative protein levels by high-resolution quantitative mass spectrometry, in a panel of lymphoblastoid cell lines (LCLs) in which we had previously measured transcript expression using RNA sequencing. We then mapped genetic variants that are associated with changes in transcript expression (eQTLs), ribosome occupancy (rQTLs), or protein abundance (pQTLs). Most of the QTLs we detected are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, we found that eQTLs tend to have significantly reduced effect sizes on protein levels, suggesting that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we confirmed the presence of a class of cis QTLs that specifically affect protein abundance with little or no effect on mRNA levels; most of these QTLs have little effect on ribosome occupancy, and hence may arise from differences in post-translational regulation.
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Project description:UBQLN2 Links Proteotoxicity with Lipid Metabolism in Neurodegeneration
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Project description:Familial neurodegenerative diseases commonly involve mutations that result in either aberrant proteins or dysfunctional components of the proteolytic machinery that acts on aberrant proteins. UBQLN2 is a ubiquitin receptor of the UBL/UBA family that binds the proteasome through its ubiquitin-like (UBL) domain and is thought to deliver ubiquitinated proteins to proteasomes for degradation. UBQLN2 mutations result in familial ALS/FTD in humans through an unknown mechanism. Quantitative multiplexed proteomics was used to provide for the first time an unbiased and global analysis of the role of Ubqln2 in controlling the composition of the proteome. We studied several murine models of Ubqln2-linked ALS and also generated Ubqln2 null mutant mice. We identified impacts of Ubqln2 on diverse physiological pathways, most notably serotonergic signaling. Interestingly, we observed upregulation of proteasome subunits, suggesting a compensatory response to diminished proteasome output. Among the specific proteins whose abundance is linked to UBQLN2 function, the strongest hits were the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Cycloheximide chase studies using induced human neurons and HEK293 cells suggested that PEG10 and TRIM32 are direct clients. Although directing the degradation of multiple proteins via the proteasome, UBQLN2 surprisingly conferred strong protection from degradation on the Gag-like protein CXX1B, which is expressed from the same family of retroelement genes as PEG10. In summary, this study charts the proteomic landscape of ALS-related Ubqln2 mutants and identifies candidate client proteins that are altered in vivo in disease models and whose degradation is promoted by UBQLN2.
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Project description:Adult polyglucosan body disease is a rare autosomal recessive neurologicla disorder with progressive paralysis, sensory deficits, and neurogenic bladder usually manifesting late in life. The disease is derived from glycogen branching enzyme deficiency that leads to aggregation of polyglucosan bodies in many cell types. This project focuses on delinating disease mechanisms in APBD through studying the proteomes of lymphoblasts of 3 patients with APBD and comparing them to several controls.
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Project description:Missense mutations in UBQLN2, a protein quality control factor, are associated with neurodegenerative diseases amyotrophic lateral sclerosis (ALS) overlapping with frontotemporal dementia (FTD). The mechanisms by which these mutations lead to neurodegeneration are not fully understood. Here we describe a critical role for UBQLN2 in regulating cellular lipid metabolism, which is crucial for cell survival under nutrient stress. The stress dependent regulation of lipid metabolism by UBQLN2 is mediated by ILVBL, a UBQLN2 substrate and a key enzyme in lipid turnover. The function of UBQLN2 in promoting ILVBL degradation and maintaining intracellular lipids was compromised by ALS/FTD-linked mutations in UBQLN2. As a result of the lipid dysregulation, synaptic vesicles were deficient and neuronal death was exacerbated in mutant UBQLN2 transgenic mice or human iPSCs derived motor neurons and cortical organoids. Replenishing lipids or restoring UBQLN2 function could reverse the deficits in the UBQLN2 mutant neurons under nutrient stress. Our study reveals UBQLN2 essential role in lipid metabolism and suggests metabolic imbalance underlying ALS/FTD and related neurodegenerative conditions.
2023-12-27 | MSV000093732 | MassIVE
Project description:The human genome is replete with sequences derived from foreign elements including endogenous retrovirus-like proteins of unknown function. The human genome is replete with sequences derived from foreign elements including endogenous retrovirus-like proteins of unknown function. Here we show that UBQLN2, a ubiquitin-proteasome shuttle factor implicated in neurodegenerative diseases, is regulated by the linked actions of two retrovirus-like proteins, RTL8 and PEG10. RTL8 confers on UBQLN2 the ability to complex with and regulate PEG10. PEG10, a core component of stress granules, drives the recruitment of UBQLN2 to stress granules under various stress conditions, but can only do so when RTL8 is present. Changes in PEG10 levels further remodel the kinetics of stress granule disassembly and overall composition by incorporating select extracellular vesicle proteins. Within stress granules, PEG10 forms virus-like particles, underscoring the structural heterogeneity of this class of biomolecular condensates. Together, these results reveal an unexpected link between pathways of cellular proteostasis and endogenous retrovirus-like proteins. we show that UBQLN2, a ubiquitin-proteasome shuttle factor implicated in neurodegenerative diseases, is regulated by the linked actions of two retrovirus-like proteins, RTL8 and PEG10. RTL8 confers on UBQLN2 the ability to complex with and regulate PEG10. PEG10, a core component of stress granules, drives the recruitment of UBQLN2 to stress granules under various stress conditions, but can only do so when RTL8 is present. Changes in PEG10 levels further remodel the kinetics of stress granule disassembly and overall composition by incorporating select extracellular vesicle proteins. Within stress granules, PEG10 forms virus-like particles, underscoring the structural heterogeneity of this class of biomolecular condensates. Together, these results reveal an unexpected link between pathways of cellular proteostasis and endogenous retrovirus-like proteins.
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