Universität zu Köln

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 ORCID: 0000-0003-2008-4582 (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:	Creators Email ORCID ORCID Put Code Wiederstein, Janica Lea UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Guenther, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Piller, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Baraldo, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kostin, Sawa UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Schindler, Natalie UNSPECIFIED orcid.org/0000-0001-7281-4597 UNSPECIFIED Sandri, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaauw, Bert UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Thomas UNSPECIFIED orcid.org/0000-0002-6165-4804 UNSPECIFIED Hoelper, Soraya UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED orcid.org/0000-0003-2008-4582 UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SIGNALING PATHWAY; ATROPHY; METHYLATION; DEGRADATION; DENERVATION; MYOPATHY; VCP/P97; DISEASE; VCP; IDENTIFICATION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18771