NAD依存型脱酸化酵素SIRT2は,プログラムされた死滅のために必要である
Nisha Narayan1, In Hye Lee, Ronen Borenstein
1Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Nature
|December 4, 2012
まとめ
SIRT2は,RIP1を脱セチル化し,RIP1-RIP3複合体の形成を防ぐことで,プログラムされた死滅を調節する. SIRT2を阻害すると,不血症-再流血などの損傷から保護され,ネクロシスの治療の可能性を示唆します.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- バイオケミストリー バイオケミストリー
背景:
- かつては制御されていないと考えられていた細胞死滅は,特定の分子経路に従っていることが理解されています.
- 腫瘍死滅因子アルファ (TNF-α) は,受容体相互作用タンパク質1 (RIP1) と受容体相互作用タンパク質3 (RIP3) の複合体の形成を通じて死滅を引き起こす.
- このRIP1-RIP3複合体の形成の調節は,ほとんど不明のままである.
研究 の 目的:
- プログラム性死滅の調節におけるSIRT2の役割を調査する.
- SIRT2がRIP1-RIP3複合体の形成を調節するかどうかを判断する.
- ネクロシスを含む状態におけるSIRT2阻害の治療の可能性を評価する.
主な方法:
- SIRT2とRIP3の構成結合が評価されました.
- SIRT2のデリエーションまたはノックダウンがマウスで実施され,RIP1-RIP3複合体の形成に対する影響が評価されました.
- TNF-α誘発性死滅は,遺伝的または薬学的SIRT2阻害の存在で測定されました.
- RIP1脱酸化と,RIP1-RIP3複合体の形成と死滅に対するその影響は,機能獲得および機能喪失の変異体を使用して分析されました.
- イシュアミア-再注射性損傷モデルを使用して,SIRT2.2のインビヴォの役割を評価しました.
主要な成果:
- SIRT2はRIP3と構成的に結合し,その欠如はRIP1-RIP3複合体の形成を防ぐ.
- SIRT2の阻害は,TNF-α誘発細胞死滅を阻害する.
- RIP1は,SIRT2依存型脱エチル化の主要標的であり,RIP1ライシン530のアセチル化により,複合体の形成と死滅を調節する.
- SIRT2の阻害は,体内において,血性不全性-再輸血性損傷から保護する.
結論:
- SIRT2は,プログラムされた死滅の重要な調節因子です.
- SIRT2を阻害剤で標的にすることは,不全性脳卒中や心筋梗塞を含む死傷に対する新しい治療戦略を提供することができる.
関連する概念動画
01:30Overview of Cell Death
7.7K
Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
7.7K
01:24Caspases
8.7K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
8.7K
01:17The Extrinsic Apoptotic Pathway
6.2K
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...
6.2K
01:31The Intrinsic Apoptotic Pathway
6.2K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.2K
01:18Autophagic Cell Death
3.3K
Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
3.3K
01:16Necrosis
5.2K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
5.2K