期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 9, 页码 6503-6517出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.309138
关键词
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资金
- National Institutes of Health [DA-004494, 1P20 DA026149, 1R01 CA124898]
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science [23570209, 23117517]
- Sao Paulo State Research Foundation
- Financiadora de Estudos e Projetos
- Brazilian National Research Council
- Grants-in-Aid for Scientific Research [23570209] Funding Source: KAKEN
The Purkinje cell degeneration (pcd) mouse has a disruption in the gene encoding cytosolic carboxypeptidase 1 (CCP1). This study tested two proposed functions of CCP1: degradation of intracellular peptides and processing of tubulin. Overexpression (2-3-fold) or knockdown (80-90%) of CCP1 in human embryonic kidney 293T cells (HEK293T) did not affect the levels of most intracellular peptides but altered the levels of alpha-tubulin lacking two C-terminal amino acids (delta2-tubulin) >= 5-fold, suggesting that tubulin processing is the primary function of CCP1, not peptide degradation. Purified CCP1 produced delta2-tubulin from purified porcine brain alpha-tubulin or polymerized HEK293T microtubules. In addition, CCP1 removed Glu residues from the polyglutamyl side chains of porcine brain alpha- and beta-tubulin and also generated a form of alpha-tubulin with two C-terminal Glu residues removed (delta3-tubulin). Consistent with this, pcd mouse brain showed hyperglutamylation of both alpha- and beta-tubulin. The hyperglutamylation of alpha- and beta-tubulin and subsequent death of Purkinje cells in pcd mice was counteracted by the knock-out of the gene encoding tubulin tyrosine ligase-like-1, indicating that this enzyme hyperglutamylates alpha- and beta-tubulin. Taken together, these results demonstrate a role for CCP1 in the processing of Glu residues from beta- as well as alpha- tubulin in vitro and in vivo.
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