Wiederstein, Janica Lea, Nolte, Hendrik, Guenther, Stefan, Piller, Tanja, Baraldo, Martina, Kostin, Sawa, Bloch, Wilhelm, Schindler, Natalie ORCID: 0000-0001-7281-4597, Sandri, Marco, Blaauw, Bert, Braun, Thomas ORCID: 0000-0002-6165-4804, Hoelper, Soraya and Krueger, Marcus (2018). Skeletal Muscle-Specific Methyltransferase METTL21C Trimethylates p97 and Regulates Autophagy-Associated Protein Breakdown. Cell Reports, 23 (5). S. 1342 - 1357. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

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 beta-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wiederstein, Janica LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piller, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baraldo, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kostin, SawaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloch, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schindler, NatalieUNSPECIFIEDorcid.org/0000-0001-7281-4597UNSPECIFIED
Sandri, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaauw, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ThomasUNSPECIFIEDorcid.org/0000-0002-6165-4804UNSPECIFIED
Hoelper, SorayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-187710
DOI: 10.1016/j.celrep.2018.03.136
Journal or Publication Title: Cell Reports
Volume: 23
Number: 5
Page Range: S. 1342 - 1357
Date: 2018
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SIGNALING PATHWAY; ATROPHY; METHYLATION; DEGRADATION; DENERVATION; MYOPATHY; VCP/P97; DISEASE; VCP; IDENTIFICATIONMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18771

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