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.