Elucidation of the physiological and pathological roles of LINCR in innate immune response with a view to creating drugs to treat sepsis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02691
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Noguchi Takuya 東北大学, 薬学研究科, 准教授 (20431893)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 自然免疫応答 / MAPキナーゼ / ユビキチン化酵素 / 炎症誘導 / Toll-like receptor

Outline of Final Research Achievements

Toll-like receptors (TLRs) drive innate immune responses via activation of intracellular signaling pathways, and play a pivotal role in host defense. Meanwhile, excessive activation of TLR signaling causes inflammatory disorders, including cytokine storm. Therefore, TLR signaling is properly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully elucidated. We identified the E3 ubiquitin ligase LINCR/ NEURL3 as a TLR signal regulator. In LINCR-knockout cells, TLR-induced JNK and p38 MAPK activation was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly reduced, indicating that LINCR positively regulates innate immune responses by promoting the JNK and p38 activation. Our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

従来の抗炎症薬は、非特異的な免疫抑制による易感染性やホルモンバランスの異常による副腎不全等の重篤な副作用を発症することがある。我々は、LINCRというユビキチン化酵素が炎症誘導の強度や持続時間を調節している仕組みを解明し、LINCRが新たな炎症性疾患の治療標的として有用である可能性を示した。将来、LINCRを標的とした薬剤を開発することで、副作用の少ない抗炎症薬の開発につながる可能性がある。