ペプチド:N-グリカナーゼによるSKN-1A/Nrf1のタンパク質配列編集 プロテアソームの遺伝子発現を制御する
Nicolas J Lehrbach1, Peter C Breen2, Gary Ruvkun1
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Cell
|April 20, 2019
まとめ
PNG-1/NGLY1酵素は,SKN-1Aタンパク質配列を編集し,N-グリコシル化アスパラジンをアスパルティック酸に変換する. このタンパク質配列の編集は,脱糖化ではなく,SKN-1Aの機能とプロテオスタシスにとって不可欠です.
科学分野:
- 分子生物学
- 細胞生物学
- プロテオスタシス
背景:
- プロテアゾームはタンパク質を分解し,プロテオトキシカルストレスによって調節されます.
- ERに関連する転写因子であるSKN-1A/Nrf1は,プロテアソーム機能障害を感知し,プロテアソーム遺伝子を上調する.
- SKN-1A/Nrf1は,N結合グリコシル化を受けます.
研究 の 目的:
- SKN-1A/Nrf1機能におけるPNG-1/NGLY1の役割を調査する.
- SKN-1A/Nrf1の活性を調節するN-リンクされたグリコシレーションのメカニズムを解明する.
- この経路がプロテオスタシスとプロテオ毒性に対する細胞抵抗にどのように貢献するのかを理解する.
主な方法:
- SKN-1A/Nrf1に対するPNG-1/NGLY1の酵素活性を調べた.
- N-グリコシライゼーション部位にアスパルテート変異を導入するために遺伝子改変を使用した.
- これらの改変がSKN-1A/Nrf1の機能とプロテアソーム活動に与える影響を評価した.
- アミロイドβペプチド毒性に対する耐性に対するSKN-1A/Nrf1過活性化の効果を調べた.
主要な成果:
- PNG-1/NGLY1は,SKN-1A/Nrf1のN-グリコシル化アスパラジン残基をアスパルチン酸に変換する.
- これらの場所でのアスパルテートの遺伝的導入は,PNG-1/NGLY1の必要性を回避し,配列編集が重要なことを示しています.
- この脱糖化に依存するタンパク質配列編集経路は,プロテアソームの発現と活性を維持するために不可欠です.
- SKN-1A/Nrf1の過剰活性化により,ヒトのアミロイドβペプチドのタンパク質毒性に対する耐性が認められる.
結論:
- N-リンクされたグリコシレーションは,デグリコシレーションに依存するタンパク質配列編集を通じてSKN-1A/Nrf1機能を調節する.
- このメカニズムは,プロテオスタシスの維持とプロテオ毒性に対する細胞防御に不可欠です.
- この経路は,哺乳類のNrf1とNrf2に類似したSKN-1イソフォームの異なる機能を説明する.
キーワード:
N結合グリコシル化NFE2L1 についてNFE2L2 についてNGLY1 についてNGLY1欠乏症Nrf1 についてNrf2 についてPNG-1 についてパンゲーゼSKN-1 についてSKN-1Aボルテゾミブ脱糖化グライコバイオロジー神経変性疾患ペプチド:N-グリカンゼプロテアソームタンパク質の品質管理タンパク質配列編集プロテオスタシスさらに関連する動画
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