アポトーシスシグナル伝達に必要なファスプレアソシエーションと,病原性突然変異による支配的抑制
R M Siegel1, J K Frederiksen, D A Zacharias
1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science (New York, N.Y.)
|July 6, 2000
まとめ
Fas受容体の変異は,自己免疫性リンパ増殖症候群におけるリンパ細胞のアポプトシスを,リガンド独立の相互作用を引き起こすことによって破壊する. 前編成のFas複合体は,Fas信号伝達と疾患に不可欠であり,ヒトの自己免疫疾患における新しいメカニズムを明らかにしています.
科学分野:
- 免疫学 免疫学とは
- 分子生物学は分子生物学である.
- 遺伝学 遺伝学とは
背景:
- 自身免疫性リンパ増殖症候群 (ALPS) は,リンパ球アポトーシスの障害によって特徴付けられます.
- Fas受容体における異性子変異は,Fas誘発のアポトーシスの支配的干渉に関与しています.
- この支配的な干渉の正確なメカニズムは,まだ完全に理解されていません.
研究 の 目的:
- ヘテロジゴスなFas変異がALPSにおけるFas誘発リンパ球アポトーシスに干渉するメカニズムを調査する.
- リガンド誘発の受容体オリゴメリゼーションまたはリガンド独立の相互作用が支配的干渉の原因であるかどうかを判断する.
- Fas信号伝達とALPSの病原性におけるFas受容体複合体の役割を明らかにする.
主な方法:
- 緑色光タンパク質 (GFP) の変種間の光共振エネルギー転送 (FRET) を利用し,生細胞内の受容体相互作用を検出しました.
- 野生型と変異Fas受容体間のリガンド独立相互作用を分析した.
- 特定の細胞外ドメインが受容体結合における役割を調査した.
主要な成果:
- 変異したFas受容体による支配的干渉は,リガンド誘発のオリゴメリゼーションに依存しないことを実証した.
- 特定細胞外ドメイン領域経由で野生型と変異Fas受容体間のリガンド独立相互作用を特定した.
- FRETを用いた生体細胞における前結合Fas複合体を観察し,その形成がリガンド結合に先行することを示した.
結論:
- 前結合したFas受容体複合体の形成は,Fas信号伝達の必要段階である.
- 野生型と変異Fas受容体間のリガンド依存の相互作用は,ヒトALPSにおける支配的干渉を誘導する.
- これらの発見は,ALPSにおける疾患病原性の新しいメカニズムを明らかにし,受容体媒介シグナル伝達において,事前形成された受容体複合体の重要性を強調しています.
関連する概念動画
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:17The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
02:26NF-kB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:17Intracellular Signaling Affects Focal Adhesions
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...