Abstract
Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.
Highlights
Homeostasis is a fundamental property of organisms and cells that allows them to remain healthy in the face of changes in the environment
Several groups have reported that polyglutamine aggregates suppress cellular functions at the transcription level, and that this suppression is accompanied by decreased acetylation of core histones
More cells expressing NES-tagged FLAG-Q79 (NES-Q79) showed a decrease in H3 and H4 acetylation than cells expressing NLS-tagged FLAG-Q79 (NLS-Q79) (Fig. 1D and supplemental Fig. S2)
Summary
Homeostasis is a fundamental property of organisms and cells that allows them to remain healthy in the face of changes in the environment. We purified FLAG-VCP from HEK293T cells expressing expanded polyglutamine tracts, analyzed it by LC/MS/MS, and found that three sequential amino acids, Ser-612, Thr-613, and Lys-614, were modified simultaneously by phosphorylation, phosphorylation, and acetylation, respectively (Fig. 2).
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