Pathophysiological roles of KLHL3-Cullin3 as a novel WNK regulatory system
| Project/Area Number |
26860629
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Wakabayashi Mai 東京医科歯科大学, 医歯(薬)学総合研究科, 非常勤講師 (00707292)
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 高血圧症 / オートファジー / WNK / KLHL3 / PHAII / p62 / 偽性低アルドステロン血症II型(PHAII) / NaCl共輸送体(NCC) / ユビキチン / E3リガーゼ / ノックインマウス / 蛍光相関分光法(FCS) |
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| Outline of Final Research Achievements |
We reported that kelch-like protein 3 (KLHL3)-Cullin3 E3 ligase ubiquitinates with-no-lysine kinase 4 (WNK4) and that impaired WNK4 ubiquitination causes pseudohypoaldosteronism type II, a hereditary hypertensive disease. As proteasome inhibition is known to activate p62-mediated selective autophagy, we investigated whether WNK4 degradation induced by KLHL3 is also mediated by such an autophagic mechanism. 3-Methyladenine, an autophagy inhibitor, blocked the epoxomicin-induced decrease in WNK4. Co-immunoprecipitation assays revealed that KLHL3 formed a complex not only with WNK4 but also with p62. Under proteasome inhibition, p62 overexpression decreased KLHL3 and WNK4 protein levels, and p62 knockdown dramatically increased KLHL3 and WNK4 protein levels. Thus, WNK4 was degraded not only by proteasomes but also by p62-KLHL3-mediated selective autophagy, which may be involved in WNK regulation under certain pathophysiological conditions.
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3.2015
Author(s)
Yoshizaki Y, Mori Y, Tsuzaki Y, Mori T, Nomura N, Wakabayashi M, Takahashi D, Zeniya M, Kikuchi E, Araki Y, Ando F, Isobe K, Nishida H, Ohta A, Susa K, Inoue Y, Chiga M, Rai T, Sasaki S, Uchida S, Sohara E.
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Journal Title
Biochem Biophys Res Commun.
Volume: 467
Issue: 2
Pages: 229-234
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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