Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover

Autoři: David Brooks aff001;  Fawwaz Naeem aff001;  Marta Stetsiv aff001;  Samantha C. Goetting aff001;  Simranjot Bawa aff001;  Nicole Green aff001;  Cheryl Clark aff001;  Arash Bashirullah aff002;  Erika R. Geisbrecht aff001
Působiště autorů: Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS, United States of America aff001;  Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, United States of America aff002
Vyšlo v časopise: Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008700
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008700


The inability to remove protein aggregates in post-mitotic cells such as muscles or neurons is a cellular hallmark of aging cells and is a key factor in the initiation and progression of protein misfolding diseases. While protein aggregate disorders share common features, the molecular level events that culminate in abnormal protein accumulation cannot be explained by a single mechanism. Here we show that loss of the serine/threonine kinase NUAK causes cellular degeneration resulting from the incomplete clearance of protein aggregates in Drosophila larval muscles. In NUAK mutant muscles, regions that lack the myofibrillar proteins F-actin and Myosin heavy chain (MHC) instead contain damaged organelles and the accumulation of select proteins, including Filamin (Fil) and CryAB. NUAK biochemically and genetically interacts with Drosophila Starvin (Stv), the ortholog of mammalian Bcl-2-associated athanogene 3 (BAG3). Consistent with a known role for the co-chaperone BAG3 and the Heat shock cognate 71 kDa (HSC70)/HSPA8 ATPase in the autophagic clearance of proteins, RNA interference (RNAi) of Drosophila Stv, Hsc70-4, or autophagy-related 8a (Atg8a) all exhibit muscle degeneration and muscle contraction defects that phenocopy NUAK mutants. We further demonstrate that Fil is a target of NUAK kinase activity and abnormally accumulates upon loss of the BAG3-Hsc70-4 complex. In addition, Ubiquitin (Ub), ref(2)p/p62, and Atg8a are increased in regions of protein aggregation, consistent with a block in autophagy upon loss of NUAK. Collectively, our results establish a novel role for NUAK with the Stv-Hsc70-4 complex in the autophagic clearance of proteins that may eventually lead to treatment options for protein aggregate diseases.

Klíčová slova:

Drosophila melanogaster – Larvae – Muscle contraction – Muscle functions – Muscle proteins – Muscle tissue – RNA interference – Sarcomeres


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