Identification of protein quality control regulators using a Drosophila model of TPI deficiency

Neurobiology of Disease

卷:152

Sabrina Swoger¹  Samantha L. Eicher¹  Sungyoun Kim¹  Andrew P.K. Wodrich¹  Maura R.Z. Ruzhnikov¹  Maria V. Lebedev¹  Tracey D. Myers²  Zachary J. Lamb³  Sherry Zheng³  Michael J. Palladino³  Hemanth Venkatesh³  Kim Gagnon³  Ana Vitantonio⁴  Ian McGrath⁴  Andreas Vogt⁴  Matthew Bruskin⁴  Stacy L. Hrizo⁴  Daniel Manjooran⁴ 

[1] Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;

[2] Department of Biology, Slippery Rock University of Pennsylvania, Slippery Rock, PA 16057, USA;

[3] Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;

[4] Department of Pharmacology &

关键词: Triosephosphate isomerase;    TPI deficiency;    Protein quality control;    Proteasome;    Molecular chaperone;    Protein degradation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPIE105Dmutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.

【 授权许可】

Unknown