RRC ID 64511
著者 Brooks D, Naeem F, Stetsiv M, Goetting SC, Bawa S, Green N, Clark C, Bashirullah A, Geisbrecht ER.
タイトル Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover.
ジャーナル PLoS Genet
Abstract 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.
巻・号 16(4)
ページ e1008700
公開日 2020-4-1
DOI 10.1371/journal.pgen.1008700
PII PGENETICS-D-19-01291
PMID 32320396
PMC PMC7176095
MeSH Actins / metabolism Animals Autophagy* Drosophila Drosophila Proteins / genetics Drosophila Proteins / metabolism* Filamins / metabolism HSC70 Heat-Shock Proteins / metabolism Muscle, Skeletal / metabolism Myosin Heavy Chains / metabolism Protein Binding Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* alpha-Crystallin B Chain / metabolism
IF 5.175
リソース情報
ショウジョウバエ DGRC#115240