Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme
Abstract
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis, and its N-terminus plays a critical role in the intracellular stability of the enzyme. In the present study, we investigated the mechanism by which the N-terminal region of TH affects this stability. TH molecules phosphorylated at their Ser31 and Ser40 were localized predominantly in the cytoplasm of PC12D cells. However, those molecules phosphorylated at Ser19 were found mainly in the nucleus, whereas they seemed to be negligible in the cytoplasm. The inhibition of proteasomes increased the quantity of TH molecules phosphorylated at their Ser19 and Ser40, although it did not increase that of TH molecules or that of TH phosphorylated at its Ser31. The inhibition of autophagy did not affect the amount of the TH molecule or that of its three phosphorylated forms. Deletion mutants of human TH type-1 lacking the N-terminal region containing the three phosphorylation sites possessed high stability of the enzyme in PC12D cells. These results suggest that the phosphorylation of the N-terminal portion of TH regulates the degradation of this enzyme by the ubiquitin-proteasome pathway.
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Phosphorylation of the N-terminal TH domain causes proteasomal degradation.
“A publication by Nakashima et al. also showed the proteasomal degradation of the TH protein and evidence that phosphorylation of the N-terminal TH domain causes proteasomal degradation [100,101].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [100]
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“Further, the inhibition of proteasome in- creased the quantity of TH phosphorylated at Ser40, which is essential for TH activity, by 2.7±0.3 fold above basal.”
BackgroundResultInfluentialNakashima, A., Ohnuma, S., Kodani, Y., Kaneko, Y. S., Nagasaki, H., Nagatsu, T., & Ota, A. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.03.022 · Cited by 22 · see citing works
Self-citation
- Authors
- Nakashima, A., Mori, K., Kaneko, Y. S., Hayashi, N., Nagatsu, T., & Ota, A.
- Affiliations
- Fujita Health University (JP)
- Tokyo Institute of Technology (JP)
- Corresponding author
- Nakashima, Akira
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 407
- Issue
- 2
- Pages
- 343-347
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2044065945
- Cited by
- 52
- References
- 21
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2021: 16 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 4
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Fujita Health University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tyrosine hydroxylase, N-terminal phosphorylation, proteasomal degradation, ubiquitin-proteasome system, protein stability, catecholamine synthesis, autophagy, nuclear localization, PC12D cells, N-terminal deletion mutants
- MeSH terms
- Animals, Autophagy, Humans, Lysosomes, Phosphorylation, Tyrosine 3-Monooxygenase, PC12 Cells, Sequence Deletion, Protein Structure, Tertiary, Ubiquitin, Proteasome Endopeptidase Complex, Rats
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