FXR-CREB軸によるオートファギーの転写制御

Sunmi Seok¹, Ting Fu¹, Sung-E Choi²

¹Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

Nature

|November 11, 2014

まとめ

ファーネソイドX受容体 (FXR) とcAMP応答要素結合タンパク質 (CREB) は,細胞自を制御する新しい軸を形成する. このFXR-CREB経路は,細胞が栄養素の供給に適応する方法を調節する.

科学分野:

細胞生物学細胞生物学
分子生物学は分子生物学である.
メタボリズムは

背景:

細胞の構成要素のリソソーマによる分解であるオートファギーは,生存とホメオスタシスにとって,特に栄養素欠乏の際に不可欠です.
キナーゼによるオートファギーの急性調節は理解されているが,その長期的な転写制御はほとんど不明である.
転写調節を理解することは,栄養状態への細胞の適応を理解する鍵です.

研究の目的:

肝臓のオートファジー遺伝子ネットワークの調節における核受容体FXRと転写活性化剤CREBの役割を調査する.
栄養素の利用可能性に応じて,FXRとCREBがオートファギーを制御する分子メカニズムを解明する.
給食と断食のサイクル中のオートファギーを支配する新しい規制軸を特定する.

主な方法:

オートファギーの調節を研究するために,FXRノックアウトマウスを含むマウスモデルを使用しました.
クロマチンの免疫プレシピテーションとハイスループットシーケンシング (ChIP-seq) を用いて,オートファジーに関連する遺伝子におけるFXRとCREBの結合部位を特定した.
規制のメカニズム的基礎を理解するために,FXR,CREB,および共同活性化器CRTC2の相互作用を調査しました.

主要な成果:

FXRの活性化は,断食状態でも,オートファギーの遺伝子を抑制し,オートファギーを抑制しました.
CREBは,栄養素欠乏時に脂質分解を促進し,FXRはこのプロセスを阻害した.
FXRとCREBは,多くのオートファジーに関連する遺伝子のプロモーター領域に結合し,78の遺伝子が共通の結合を示す.
FXRはCREB-CRTC2複合体を破壊することでオートファギーを阻害し,Atg7,Ulk1,Tfeb.のような重要なオートファギーの遺伝子を抑制します.

結論:

肝臓のオートファギーの調節のための重要な生理学的スイッチとして機能する新しいFXR-CREBシグナル伝達軸を特定しました.
この軸は,給食と断食のサイクル中にオートファギーの持続的な栄養分調節を提供することを実証しました.
この発見は,栄養素の変動に対する細胞の適応を制御する分子機構に関する新しい洞察を提供します.

さらに関連する動画

08:34

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

Published on: June 3, 2016

15.9K

06:58

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

1.4K

関連する概念動画

01:27

Autophagy

6.5K

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...

6.5K

02:23

Master Transcription Regulators

8.1K

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...

8.1K

01:45

Regulation of Nuclear Protein Sorting

3.5K

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...

3.5K

01:31

Regulation of the Unfolded Protein Response

3.3K

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...

3.3K

01:23

Regulation of Expression at Multiple Steps

1.6K

The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...

1.6K

01:18

Autophagic Cell Death

5.1K

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...