Skeletal Muscle-Specific Methyltransferase METTL21C Trimethylates p97 and Regulates Autophagy-Associated Protein Breakdown
Open accessAbstract
Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c −/− muscles. In addition, we demonstrate that METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo . We conclude that the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions.
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Mettl21e negatively regulates 26S proteasome activity, while Mettl21c is crucial for autophagy regulation.
“While Mettl21e negatively regulates 26S proteasome activity, Mettl21c seems to be crucial for autophagy regulation.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [62]
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References 57 · Cited by 52
Research works printed but not linked: 2
- Klionsky, D.J. (2005). Autophagy. Curr. Biol. 15 , R282-R283. http://refhub.elsevier.com/S2211-1247(1830524-2/sref27)
- Lilienbaum, A. (2013). Relationship between the proteasomal system and autophagy. Int. J. Biochem. Mol. Biol. 4 , 1-26. http://refhub.elsevier.com/S2211-1247(1830524-2/sref32)
- Authors
- Wiederstein, J. L., Nolte, H., Günther, S., Piller, T., Baraldo, M., Kostin, S., Bloch, W., Schindler, N., Sandri, M., Blaauw, B., Braun, T., Hölper, S., & Krüger, M.
- Affiliations
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Max Planck Institute for Heart and Lung Research (DE)
- Goethe University Frankfurt (DE)
- University of Padua (IT)
- German Sport University Cologne (DE)
- Johannes Gutenberg University Mainz (DE)
- Sanofi (Germany) (DE)
- University of Cologne (DE)
- Corresponding author
- Hölper, Soraya
- Krüger, Marcus
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 23
- Issue
- 5
- Pages
- 1342-1356
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2802256034
- Cited by
- 52
- References
- 57
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 13 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 1
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc-nd)
- Padua Research Archive (University of Padova) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Funders
- DFG Excellence Cluster Cardio-Pulmonary System
- Cologne Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases (CECAD) EXC 299/2
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- lysine methyltransferase, VCP, skeletal muscle, autophagy, protein degradation, multisystem proteinopathy, denervation-induced muscle atrophy, autophagosomes, endurance capacity, p62, cathepsins, MYH7, protein aggregates
- MeSH terms
- Valosin Containing Protein, Animals, Autophagy, Male, Methylation, Methyltransferases, Mice, Knockout, Muscle, Skeletal, Mice, Proteolysis
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