ZAKα誘発のリボ毒性ストレス反応は,ヒトNLRP1炎症体を活性化させる

Kim S Robinson^1,2, Gee Ann Toh³, Pritisha Rozario³

¹Skin Research Institute of Singapore (SRIS), 308232 Singapore.

Science (New York, N.Y.)

|July 20, 2022

まとめ

人間のNLRP1は,先天的な免疫センサーで,紫外線B (UVB) と毒素をリボ毒性ストレス反応 (RSR) で検出します. 皮の免疫とRSRの仕組みに新たな洞察を与えてくれます

科学分野:

免疫学
細胞生物学
分子生物学

背景:

人間のNLRP1は,皮膚と呼吸道上の重要な免疫センサーです.
リボ毒性ストレス反応 (RSR) は,毒素や環境ストレスによって活性化される細胞の防御メカニズムです.
RSRを検出するNLRP1の役割とその下流効果は,まだ完全に理解されていません.

研究の目的:

リボ毒性ストレス反応 (RSR) の感知におけるヒトNLRP1の役割を調査する.
NLRP1がUVBと毒素を検出する分子メカニズムを解明する.
NLRP1の活性化がピロプトーシスにつながり,その影響がケラチノサイトに及ぼすかどうかを判断する.

主な方法:

MAP3K20/ZAKαとp38キナーゼによるNLRP1のリン酸化を研究する生化学分析.
NLRP1のリン酸化部位のサイト指向型変異.
ピロプトーシス誘導を評価するためにヒトのケラチノサイトで機能的測定法.
NLRP1ドメインを融合させ,最小の炎症体センサーを設計する.

主要な成果:

人間のNLRP1は,UVBとリボトキシン誘発のRSRを直接感知します.
RSRは,ZAKαとp38によって特定のNLRP1リンクル領域 (NLRP1^DR) の高酸化を引き起こす.
NLRP1^DRにおける単一のZAKαリン酸化部位変異は,UVBおよびリボトキシン誘発の熱滅亡を阻害する.
NLRP1^DRをCARD8と融合させ,RSRセンシングを可能にする最小の炎症体センサーが作成されました.

結論:

NLRP1は,ヒトのケラチノ細胞におけるUVBとリボトキシン誘発のRSRの重要なセンサーです.
NLRP1媒介の熱死は,RSR経路の不可欠な部分です.
これらの発見は,皮膚におけるUVB感知の理解を深め,NLRP1アゴニストとしてのリボトキシンを特定します.

さらに関連する動画

09:04

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

21.0K

10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.3K

関連する概念動画

01:31

Regulation of the Unfolded Protein Response

2.6K

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...

2.6K

02:26

NF-κB-dependent Signaling Pathway

7.8K

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...

7.8K

01:23

Stringent Response in E. coli

Bacterial growth is closely tied to nutrient availability, with cells proliferating exponentially under favorable conditions and entering a stationary phase when resources become scarce. This transition is mediated by a regulatory mechanism known as the stringent response, which allows bacteria to adapt to nutrient deprivation by modulating gene expression and metabolic activity.During nutrient scarcity, intracellular amino acid levels decline. It results in the accumulation of uncharged tRNAs...

01:30

Other Stress Responses in Bacteria

Bacteria have global regulatory systems that control several types of stress mechanisms. These include Pho regulon and the heat shock response, which are essential systems for environmental adaptation, such as nutrient limitation and proteotoxic stress. The Pho regulon and the heat shock response exemplify bacterial resilience, enabling rapid adaptation to fluctuating environmental conditions.Pho RegulonBacteria require phosphorus for essential cellular processes, including nucleic acid...

01:37

The Unfolded Protein Response

5.0K

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...

5.0K

01:31

The Intrinsic Apoptotic Pathway

6.8K

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...