Mechanism of plasma membrane expression of endoplasmic reticulum chaperone proteins

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07504
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: ISHIGAKI HIROHITO 滋賀医科大学, 医学部, 准教授 (90432301)
• Co-Investigator(Kenkyū-buntansha): 伊藤 靖 滋賀医科大学, 医学部, 教授 (90324566)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: GRP94 / RAGE / IL-6 / 癌免疫

Outline of Final Research Achievements

GRP94 is a protein present in the endoplasmic reticulum in normal cells. In cancer cells, GRP94 is known to be expressed at the plasma membrane, but the protein that anchors it to the membrane (anchor protein) is unknown. In this study, we attempted to identify the anchor protein of GRP94. We found that a cancer cell release GRP94 to the extracellular space, and that the released GRP94 binds to RAGE on the plasma membrane. In addition, it has been reported that signals from RAGE induce IL-6, the cancer cell produced IL-6 only when GRP94 was added to the cells. In the cancer cell, GRP94 was found to be present on the plasma membrane bound to RAGE and may induce the production of IL-6.

Free Research Field

癌免疫学

Academic Significance and Societal Importance of the Research Achievements

癌免疫において、RAGEのリガンドとしては、これまでHMGB1やS100等が知られていたが、今回の我々の検討で、GRP94も新規のRAGEのリガンドとして示された。またGRP94はRAGEに結合して、癌細胞からのIL-6の産生を誘導する可能性が示された。IL-6は樹状細胞の成熟障害や、癌環境下での免疫疲労に関与しており、腫瘍の分泌したGRP94がautocrineに働くことでIL-6を産生し、癌環境下での免疫疲労を誘導している可能性が示された。新規癌免疫療法のターゲットとしてGRP94やRAGE、IL-6が有望であると考えられた。