Elucidation of physiological function of ubiquitin ligase RNF183 and development of new therapeutic agent for inflammatory bowel desease

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16373
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Nagasaki University (2020); Hiroshima University (2019)
• Principal Investigator: OKAMOTO Takumi 長崎大学, 医歯薬学総合研究科(薬学系), 特任研究員 (40826351)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: ユビキチンリガーゼ / RNF183 / 炎症性腸疾患 / 潰瘍性大腸炎 / クローン病

Outline of Final Research Achievements

In recently, it has reported that the expression of ubiquitin ligase RNF183, which is originally expressed specifically in the collecting duct of the kidney, is increased in the large intestine of patients with inflammatory bowel disease. Although RNF183 is specifically expressed in the kidney, the substrate protein has not been identified and its physiological function is unknown. In this study, we succeeded in identifying the substrate proteins of RNF183 and clarified that RNF183 promotes lysosomal degradation of ion transporters Na, K-ATPase and NKCC1. The expression of Na, K-ATPase and NKCC1 has been reported to be decreased in the large intestine of IBD patients, suggesting that the increased expression of RNF183 is involved in the pathophysiology of IBD. We also indicated that the proximal biotin labeling method using biotin ligase is useful for identifying the substrate proteins of ubiquitin ligases.

Free Research Field

生化学・分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ユビキチンリガーゼと基質タンパク質は結合が弱く、一過性であることが多いため、基質タンパク質の同定が困難であった。しかし、本研究によりビオチンリガーゼを用いた近位ビオチン標識法がユビキチンリガーゼの基質タンパク質同定に有用であることを示し、ユビキチンリガーゼの研究において、その学術的意義は大きい。また、RNF183が高浸透圧ストレスにより発現誘導されるため、IBDの発症に高浸透圧ストレスが関与するという新たな知見を提示しており、社会に与えるインパクトは大きなものであると考えられる。