JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us
このページは機械翻訳されています。他のページは英語で表示される場合があります。 View in English

新しいミトコンドリアDNA合成により,NLRP3炎症体の活性化が可能

  • 0Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Nature +

|

2018年7月27日

|

2018年7月27日

PubMedで要約を見る

まとめ

この要約は機械生成です。

CMPK2によって調節されるミトコンドリアDNA (mtDNA) 合成は,慢性炎症性疾患におけるNLRP3炎症体の活性化に不可欠である. この発見は 炎症を制御する 新しい治療目標を提供します

科学分野

  • 免疫学
  • 分子生物学
  • 細胞生物学

背景

  • NLRP3の炎症性活性が調節不良で 慢性的な炎症や疾患を誘発する
  • ミトコンドリアの損傷はNLRP3炎症体の活性化に必要であることが知られている.
  • マクロファージが様々なNLRP3活性化剤を感知する正確なメカニズムは不明である.

研究 の 目的

  • NLRP3炎症体の活性化におけるミトコンドリアDNA (mtDNA) 合成の役割を明らかにする.
  • トール型受容体 (TLR) のエンゲージメントとNLRP3のシグナリングを結びつける分子経路を特定する.
  • NLRP3炎症関連疾患を標的とした潜在的な治療戦略を探求する.

主な方法

  • NLRP3シグナル発信におけるトール型受容体 (TLR) とそのアダプター (MyD88,TRIF) の役割を調査した.
  • IRF1依存のCMPK2の転写とデオキシリボヌクレオチド合成への影響を分析した.
  • 酸化したmtDNA断片を生成するためのCMPK2依存型mtDNA合成の必要性を検討した.
  • NLRP3炎症体複合体との細胞塩基酸化mtDNAの関連性を評価した.

主要な成果

  • IRF1依存CMPK2によるミトコンドリアDNA (mtDNA) 合成を誘導する.
  • CMPK2依存のmtDNA合成は,NLRP3の活性化時に酸化したmtDNA断片を生成するために重要である.
  • サイトゾリック酸化されたmtDNA断片は,NLRP3炎症体の活性化に直接関連し,必要である.
  • CMPK2の触媒活動は,NLRP3炎症体シグナル伝達における重要な調節点として特定されています.

結論

  • CMPK2によって調整されるミトコンドリアDNA合成は,NLRP3炎症体の活性化にとって重要な上流イベントです.
  • 酸化されたmtDNA断片は,TLRの関与と炎症体の組み立てを結びつける重要な信号として機能する.
  • CMPK2の活性を標的とした治療は,NLRP3炎症体によって引き起こされる慢性炎症疾患の管理に有望な治療法です.

関連する概念動画

Animal Mitochondrial Genetics 02:59

9.3K

Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...

Comparing Mitochondrial, Chloroplast, and Prokaryotic Genomes 02:16

16.4K

The present-day mitochondrial and chloroplast genomes have retained some of the characteristics of their ancestral prokaryotes and also have acquired new attributes during their evolution within eukaryotic cells. Like prokaryotic genomes, mitochondrial and chloroplast genomes neither bind with histone-like proteins nor show complex packaging into chromosome-like structures, as observed in eukaryotes. Unlike mitotic cell divisions observed in eukaryotic cells, mitochondria and chloroplasts...

Export of Mitochondrial and Chloroplast Genes 02:19

4.2K

A eukaryotic cell can have up to three different types of genetic systems: nuclear, mitochondrial, and chloroplast. During evolution, organelles have exported many genes to the nucleus; this transfer is still ongoing in some plant species. Approximately 18% of the Arabidopsis thaliana nuclear genome is thought to be derived from the chloroplast’s cyanobacterial ancestor, and around 75% of the yeast genome derived from the mitochondria’s bacterial ancestor. This export has occurred...

Lagging Strand Synthesis 01:59

61.4K

During replication, the complementary strands in double-stranded DNA are synthesized at different rates. Replication first begins on the leading strand. Replication starts later, occurs more slowly, and proceeds discontinuously on the lagging strand.
There are several major differences between synthesis of the leading strand and synthesis of the lagging strand. 1) Leading strand synthesis happens in the direction of replication fork opening, whereas lagging strand synthesis happens in the...

DNA Replication 02:40

59.6K

DNA replication involves the separation of the two strands of the double helix, with each strand serving as a template from which the new complementary strand is copied.  After replication, each double-stranded DNA includes one parental or “old” strand and one “new” strand. This is known as semiconservative replication. The resulting DNA molecules have the same sequence and are divided equally into the two daughter cells.
Replication in Prokaryotes
DNA replication...

From DNA to Protein 03:06

22.5K

The flow of genetic information in cells from DNA to mRNA to protein is described by the central dogma, which states that genes specify the sequence of mRNAs, which in turn specify the sequence of amino acids making up all proteins. The decoding of one molecule to another is performed by specific proteins and RNAs. Because the information stored in DNA is so central to cellular function, it makes intuitive sense that the cell would make mRNA copies of this information for protein synthesis...