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Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9-engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B's role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD-linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.
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Created: 9th Jul 2024 at 13:14
Last updated: 15th Oct 2024 at 12:09
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Projects: SyNergy - Published Datasets
Institutions: DZNE
Projects: SyNergy - Published Datasets
Institutions: DZNE
Projects: SyNergy - Published Datasets
Institutions: Max Planck Institute for Biological Intelligence
Projects: SyNergy - Published Datasets, HTRA1
Institutions: Klinikum der Universität München
Public web page: Not specified
Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa, Danio rerio
Submitter: Rainer Malik
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Assays: Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Bottom-up proteomics (mouse), Gel-based experiment (human), Phosphoproteomics / Bottom-up proteomics (mouse), Proximity-proteomics-based autophagosome content profiling (human), SWATH MS (human), SWATH MS (mouse), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (macaque), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (rat), Untargeted Proteomics (mouse)
Snapshots: Snapshot 1
LCL cells were cultured in lysine- and arginine-free DMEM (GIBCO) supplemented with 2 mM glutamine, 10% dialyzed FBS and antibiotics as well as with 146 mg/ml light (K0, Sigma) or heavy lysine (K8, Cambridge Isotope Laboratories) and 84 mg/ml light (R0, Sigma) or heavy (R10, CambridgeIsotope Laboratories) arginine, respectively. Cell pellets were lysed in 8 M Urea in 50 mM Tris-HCl pH 8.0. Protein concentrations were determined by a BCA assay and protein amounts were adjusted to equal concentrations. ...
Submitter: Rainer Malik
Assay type: Proteomics
Technology type: Technology Type
Investigation: Proteomics
Organisms: Homo sapiens
SOPs: No SOPs
Data files: Phosphoproteomic analysis of UBQLN2 mutant cells, Whole-cell abundance profiling and interaction ...
Snapshots: No snapshots
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 ...
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
Investigations: Proteomics
Studies: Multi-omics profiling identifies a deregulated ...
Assays: Shotgun proteomics (human)
In the project “Phosphoproteomic analysis of UBQLN2 mutant cells” by Laura Strohm, Zehan Hu, Jörn Dengjel, and Christian Behrends eight sets of SILAC experiments were performed, two times four biological replicates, comparing proteome and phosphoproteome of control and UBQLN2 mutant, patient-derived lymphoblasts (LCLs).
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
Investigations: Proteomics
Studies: Multi-omics profiling identifies a deregulated ...
Assays: Shotgun proteomics (human)
Abstract (Expand)
Authors: L. Strohm, Z. Hu, Y. Suk, A. Ruhmkorf, E. Sternburg, V. Gattringer, H. Riemenschneider, R. Berutti, E. Graf, J. H. Weishaupt, M. S. Brill, A. B. Harbauer, D. Dormann, J. Dengjel, D. Edbauer, C. Behrends
Date Published: 1st Jul 2022
Publication Type: Journal
PubMed ID: 35777956
Citation: Life Sci Alliance. 2022 Jul 1;5(11):e202101327. doi: 10.26508/lsa.202101327. Print 2022 Nov.