C15ORF48 is the inducing factor of thymic autophagy that regulates autoimmunity.

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20706
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Chiba University
• Principal Investigator: Takakura Yuki 千葉大学, 大学院薬学研究院, 特任研究員 (70963007)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 胸腺 / オートファジー / ミトコンドリア / 自己免疫 / 上皮細胞

Outline of Final Research Achievements

TECs (Thymic epithelial cells) show high autophagy activity without starvation. This implies that such stress-independent autophagy might contribute to self-protein degradation for generating self-antigen peptides in TECs. Consistently, autophagy in TECs is important for acquisition of T cell self-tolerance. However, the mechanism by which TECs induce autophagy in the absence of starvation is unknown. We found novel autophagy-inducing factor C15ORF48 in TECs.C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream ULK1. C15ORF48-/- mice show a reduction in stress-independent autophagy in TECs. Moreover, C15ORF48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating self-tolerance.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

胸腺上皮細胞では恒常的なオートファジーの誘導が報告されているが、オートファジーは飢餓応答時に誘導されると広く認識されており、飢餓非依存的なオートファジー誘導機構はあまりよくわかっていない。我々はC15ORF48を飢餓非依存的オートファジー誘導因子として同定しており、本研究成果は免疫システムのみならずオートファジーの基礎研究においても学術的に重要な知見を与え得るものと考えている。