ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Jordan D FuquaVitor A Lira

Abstract

Basal protein turnover, which largely relies on the degradation of ubiquitinated substrates, is instrumental for maintenance of muscle mass and function. However, the regulation of ubiquitinated protein degradation in healthy, nonatrophying skeletal muscle is still evolving, and potential tissue-specific modulators remain unknown. Using an unbiased expression analysis of 34 putative autophagy genes across mouse tissues, we identified unc-51 like autophagy activating kinase (Ulk)2, a homolog of the yeast autophagy related protein 1, as particularly enriched in skeletal muscle. Subsequent experiments revealed accumulations of insoluble ubiquitinated protein aggregates associated with the adaptors sequestosome 1 (SQSTM1, also known as p62) and next to breast cancer type 1 susceptibility protein gene 1 protein (NBR1) in adult muscles with ULK2 deficiency. ULK2 deficiency also led to impaired muscle force and caused myofiber atrophy and degeneration. These features were not observed in muscles with deficiency of the ULK2 paralog, ULK1. Furthermore, short-term ULK2 deficiency did not impair autophagy initiation, autophagosome to lysosome fusion, or protease activities of the lysosome and proteasome. Altogether, our results indicate t...Continue Reading

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Citations

Aug 14, 2020·American Journal of Physiology. Cell Physiology·David C HughesSue C Bodine
Jul 9, 2020·International Journal of Molecular Sciences·Anna Vainshtein, Marco Sandri
Nov 20, 2020·Journal of Applied Physiology·Luís G O de SousaSue C Bodine
Jan 14, 2021·Nature Communications·Roberta SartoriMarco Sandri
Oct 30, 2020·Cells·Anna Vainshtein, Paolo Grumati
Dec 29, 2020·Frontiers in Cell and Developmental Biology·Cristiana PerrottaClara De Palma
Dec 12, 2020·International Journal of Molecular Sciences·Juan Carlos RiveraClaudio Cabello-Verrugio
Mar 7, 2021·International Journal of Molecular Sciences·Anna S NichenkoJarrod A Call
Apr 1, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Amy D HannaSusan L Hamilton

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Methods Mentioned

BETA
ubiquitination
PCR
transfect

Software Mentioned

DAVID
Dynamic Muscle Analysis
ASI
ImageJ
Prism
gcrma
GraphPad

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