Elucidation of the regulatory mechanisms of ASK1 ubiquitination for developing a new treatment strategy for ASK1-related diseases

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K18856
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Hirata Yusuke 東北大学, 薬学研究科, 助教 (10748221)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: ASK1 / Roquin-2 / TRIM48 / ユビキチン化 / TLR4

Outline of Final Research Achievements

Roquin-2 is a ubiquitin ligase that ubiquitinates a stress-responsive kinase ASK1. In this study, we identified another ubiquitination target of Roquin-2 that functions in TLR4 (the receptor for a bacterial component, LPS) signaling pathway. We found that Roquin-2 promotes ubiquitin-dependent degradation of ASK1 and the newly found target molecule, and thereby negatively regulates innate immune responses. Meanwhile, we also identified another ubiquitin ligase TRIM48 as a positive regulator of ASK1 activation. TRIM48 promotes ASK1 activation, and thus facilitates ASK1 ubiquitination mediated by Roquin-2. These findings provide comprehensive understanding of the regulatory mechanisms for ASK1 ubiqutination, which will lead to the development of novel therapeutic strategies for ASK1-related diseases.

Free Research Field

細胞内シグナル伝達、ストレス応答、自然免疫