Janica Lea Wiederstein, Hendrik Nolte, Stefan Günther, Tanja Piller, Martina Baraldo, Sawa Kostin, Wilhelm Bloch, Natalie Schindler, Marco Sandri, Bert Blaauw, Thomas Braun, Soraya Hölper, Marcus Krüger
- 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.
MetadatenAuthor: | Janica Lea Wiederstein, Hendrik Nolte, Stefan GüntherORCiD, Tanja PillerORCiD, Martina Baraldo, Sawa KostinORCiD, Wilhelm Bloch, Natalie Schindler, Marco Sandri, Bert Blaauw, Thomas BraunORCiDGND, Soraya Hölper, Marcus KrügerORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-511143 |
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DOI: | https://doi.org/10.1016/j.celrep.2018.03.136 |
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ISSN: | 2211-1247 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/29719249 |
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Parent Title (English): | Cell reports |
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Publisher: | Cell Press ; Elsevier |
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Place of publication: | Maryland Heights, MO ; [New York, NY] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/05/02 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2019/10/16 |
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Tag: | atrophy; autophagy; methyltransferases; p97; skeletal muscle |
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Volume: | 23 |
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Issue: | 5 |
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Page Number: | 16 |
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First Page: | 1342 |
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Last Page: | 1356 |
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Note: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
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HeBIS-PPN: | 455330913 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |
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