1. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle
- Author
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Luís G O de Sousa, Scott M. Ebert, Ana Kronemberger, Ling Yang, Sue C. Bodine, Jay Blomme, Dam Bae, Christopher M. Adams, Matthew P. Harris, Caleb Mere, Jordan D. Fuqua, Mitchell Edwards, Kristen D. Turner, Vitor A. Lira, and Estevão Scudese
- Subjects
0301 basic medicine ,Male ,autophagy ,Protein degradation ,Protein Serine-Threonine Kinases ,Biochemistry ,03 medical and health sciences ,Protein Aggregates ,0302 clinical medicine ,Ubiquitinated Protein Degradation ,Sequestosome 1 ,Genetics ,medicine ,Myocyte ,Animals ,Homeostasis ,education ,aggrephagy ,Muscle, Skeletal ,Molecular Biology ,ULK1 ,Adaptor Proteins, Signal Transducing ,education.field_of_study ,proteostasis ,Chemistry ,Research ,Autophagy ,p62 ,Protein turnover ,Autophagosomes ,Ubiquitination ,Skeletal muscle ,NBR1 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Proteostasis ,Lysosomes ,030217 neurology & neurosurgery ,Biotechnology - 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 that skeletal muscle ULK2 has a unique role in basal selective protein degradation by stimulating the recognition and proteolytic sequestration of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. These findings have potential implications for conditions of poor protein homeostasis in muscles as observed in several myopathies and aging.-Fuqua, J. D., Mere, C. P., Kronemberger, A., Blomme, J., Bae, D., Turner, K. D., Harris, M. P., Scudese, E., Edwards, M., Ebert, S. M., de Sousa, L. G. O., Bodine, S. C., Yang, L., Adams, C. M., Lira, V. A. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle.
- Published
- 2019