NK細胞受容体NKp46は,ERストレスを受けた細胞でエクトカルレチクリンを認識する
Sumit Sen Santara1,2,3, Dian-Jang Lee1,2, Ângela Crespo1,2
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Nature
|April 5, 2023
まとめ
自然キラー細胞はNKp46を使用して,ストレスを受けた細胞の外部化されたカルレチクリン (ecto-CRT) を認識します. この相互作用はNK細胞の信号伝達と殺戮を誘発し,化学療法による細胞死と腫瘍の排除に不可欠です.
科学分野:
- 免疫学
- 細胞生物学
- 癌 研究
背景:
- 自然殺虫細胞 (NK細胞) は,受容体を活性化することで,感染した,変異した,またはストレスを受けた細胞を排除します.
- NKp46は,ほとんどのNK細胞といくつかの先天性リンパ球細胞の重要な活性化受容体です.
- NKp46の内生リガンドは未確認のままである.
研究 の 目的:
- NKp46受容体の内生リガンドを特定する.
- NK細胞媒介の細胞毒性におけるNKp46-リガンドの相互作用の役割を明らかにする.
- 癌と病気におけるこの相互作用を標的とした治療の可能性を調査する.
主な方法:
- エンドプラズマ網膜 (ER) ストレス中の外部化されたカルレチクリン (ecto- CRT) のNKp46認識を調査した.
- CALRの遺伝子ノックアウト/ノックダウンとNKp46の機能を評価するために抗体のブロックを使用した.
- NKp46媒介の腫瘍制御を評価するために,メラノーマと肺がんのマウスモデルを使用した.
主要な成果:
- NKp46は,ERストレス中に細胞表面に転移するecto-CRTを直接認識します.
- 癌細胞,ウイルス感染細胞,老化細胞のNKp46媒介による死は,ecto- CRTに依存しています.
- NKp46- ecto- CRTの相互作用は,NK細胞のデグラニュレーションとサイトカインの分泌を含む抗腫瘍免疫を強化する.
結論:
- NKp46は,危険に関連した分子パターン (DAMP) としてecto-CRTを認識します.
- この認識経路は,ERストレス細胞を排除し,抗腫瘍免疫に貢献します.
- NKp46-ecto-CRT軸をターゲットにすることは,がん免疫療法の有望な戦略です.
関連する概念動画
01:31Regulation of the Unfolded Protein Response
2.5K
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...
2.5K
01:17Role of ER in the Secretory Pathway
5.5K
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
5.5K
01:29Protein Folding Quality Check in the RER
3.8K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.8K
01:15Receptor Downregulation in MVBs
2.1K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.1K
01:37The Unfolded Protein Response
4.8K
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...
4.8K
01:45ER Retrieval Pathway
3.9K
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
3.9K