Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulates autophagy-associated protein breakdown

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