Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

摘要: Congenital deficiencies of the human pyruvate dehydrogenase (PDH) complex are considered to be due loss function mutations in one component enzymes. Here we describe a case PDH deficiency associated with E1β subunit (PDHB) gene. The clinical phenotype patient was consistent reported cases deficiency. Cultured skin fibroblasts demonstrated 55% reduction activity and markedly decreased immunoreactivity for PDHB protein, compared healthy controls. Surprisingly, nucleotide sequence analyses cDNAs corresponding E1α (PDHA1) genes revealed no pathological mutations. Moreover, relative expression level mRNA rates transcription translation gene were normal. However, PDC could restored cells from this following treatment MG132, specific proteasome inhibitor, normal levels detected MG132-treated cells. Similar results obtained Tyr-phostin 23 (Tyr23), inhibitor epidermal growth factor receptor-protein-tyrosine kinase (EGFR-PTK), which also protein those subjects or patients PDHA1 index patient's contained high basal EGFR-PTK that correlated ubiquitination cellular proteins, although total EGFR similar Elα-deficient subjects. These data indicate our involves post-translational modification EGFR-PTK-mediated tyrosine phosphorylation leads enhanced followed by proteasome-mediated degradation. They provide novel mechanism accounting congenital perhaps other inborn errors metabolism.