Elucidation of molecular mechanisms for reassembling the nuclear lamina and NPCs

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06617
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Takeshi Shimi 東京工業大学, 科学技術創成研究院, 特任准教授 (60817568)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 核ラミナ / ラミン / 核膜孔複合体 / ヌクレオポリン / BAF / cGAS

Outline of Final Research Achievements

In mammalian cell nuclei, the nuclear lamina (NL) underlies the nuclear envelope to maintain nuclear structure. The major structural components of the NL, the nuclear lamins are involved in the protection against NE rupture induced by mechanical stress. A-type lamins are derived from the single gene LMNA by alternative splicing to produce long and short splicing variants, lamin A (LA) and lamin C (LC), respectively. Numerous LMNA mutations are known to cause human genetic disorders collectively called as laminopathies. We revealed that among all the lamin isoforms, only nucleoplasmic LC rapidly accumulated at the rupture sites. Some of laminopathy mutations in the immunoglobulin-like fold domain of LC disrupted the binding to BAF, leading to the inhibition of the recruitment from the nucleoplasm to the rupture sites. BAF accumulation at the rupture sites and DNA sensing of cytoplasmic cGAS were partially dependent on LA/C.

Free Research Field

核膜の構造と機能に関する細胞生物学的研究

Academic Significance and Societal Importance of the Research Achievements

本研究では、ラミンCが破損した核膜に迅速に集積し、核膜の修復機構に関与することが明らかとなった。さらに、ラミンの変異が原因するラミノパシーにおいて、核膜の修復機構に遅延が生じることが判明した。これらの研究成果は、破壊した核膜の修復と核膜の恒常的な維持を行う分子機構の解明につながるという観点から細胞生物学的な意義が高いだけでなく、核膜の破損を伴う早老症、心筋症、筋ジストロフィーに代表されるラミノパシーの分子レベルでの病態解明と新規治療戦略の探索などの応用研究へと展開する可能性があると考えられる。