Integrated understanding of protein function regulated by mucin-type O-glycans

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K05984
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Kudo Takashi 筑波大学, 医学医療系, 准教授 (20288062)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 糖鎖 / ノックアウトマウス / 糖転移酵素 / 糖タンパク質 / ムチン型糖鎖 / シアル酸

Outline of Final Research Achievements

Cosmc, a C1galt1-specific molecular chaperone, is required for normal folding of C1galt1, which synthesizes the mucin-type glycan core 1 structure. To investigate the physiological roles of core 1-derived glycans, we generated Cosmc-conditional knockout (cKO) mice using various Cre driver mice. The ubiquitous and inducible cKO mice exhibited rapid weight loss in the thymus, adipose tissue, and pancreas, along with atrophy of white and brown adipose tissues, spontaneous gastric ulcers, severe renal dysfunction, and mortality around 10 days post-induction. Furthermore, analysis of St6galnac3 and St6galnac4 double knockout mice, which lack sialic acid addition to the mucin-type O-glycan chain, revealed that sialic acid deficiency in podoplanin led to hemorrhage in the mesenteric lymph nodes.

Free Research Field

解剖学

Academic Significance and Societal Importance of the Research Achievements

今回の研究成果からムチン型糖鎖が失われることによる複数の臓器に異常きたし、多臓器不全で死亡することが判明した。個々の臓器の表現型異常の分子レベルでの機序については今後の課題となるが、ムチン型糖鎖が各臓器の恒常性の維持に必須であることが明らかになった。多臓器不全を引き起こすメカニズム解明は、糖鎖生物学の新しい研究方向を提示し、糖鎖修飾の役割理解を深める基礎となります。また、ムチン型糖鎖異常の理解は、疾患の治療法や診断方法の開発に繋がり、バイオテクノロジー分野の技術進展を促します。