Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
| Autor: | Laura Strohm, Zehan Hu, Yongwon Suk, Alina Rühmkorf, Erin Sternburg, Vanessa Gattringer, Henrick Riemenschneider, Riccardo Berutti, Elisabeth Graf, Jochen H Weishaupt, Monika S Brill, Angelika B Harbauer, Dorothee Dormann, Jörn Dengjel, Dieter Edbauer, Christian Behrends |
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| Rok vydání: | 2022 |
| Předmět: |
genetics [Microtubule-Associated Proteins]
Proteomics Health Toxicology and Mutagenesis genetics [Autophagy-Related Proteins] Autophagy-Related Proteins Plant Science Biochemistry Genetics and Molecular Biology (miscellaneous) metabolism [Autophagy-Related Proteins] metabolism [Adaptor Proteins Signal Transducing] MAP1B protein human ddc:570 genetics [Adaptor Proteins Signal Transducing] Humans metabolism [Transcription Factors] genetics [RNA] genetics [Frontotemporal Dementia] Adaptor Proteins Signal Transducing metabolism [RNA-Binding Protein FUS] Ecology metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis metabolism [Microtubule-Associated Proteins] genetics [Transcription Factors] FUS protein human microtubule-associated protein 1B genetics [Amyotrophic Lateral Sclerosis] metabolism [RNA] Frontotemporal Dementia metabolism [Frontotemporal Dementia] RNA RNA-Binding Protein FUS genetics [RNA-Binding Protein FUS] Microtubule-Associated Proteins UBQLN2 protein human HeLa Cells Transcription Factors |
| Zdroj: | Life science alliance 5(11), e202101327 (2022). doi:10.26508/lsa.202101327 |
| ISSN: | 2575-1077 |
| DOI: | 10.26508/lsa.202101327 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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