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정다혜Da-Hye Jeong
아주대학교 의과대학
Adv. Sci., 08 February 2025 | https://doi.org/10.1002/advs.202412393
Optogenetically Activatable MLKL as a Standalone Functional Module for Necroptosis and Therapeutic Applications in Antitumoral Immunity
Da-Hye Jeong 1 2, Seokhwi Kim 2 3, Han-Hee Park 1 2, Kyoung-Jin Woo 2, Jae-Il Choi 3, Minji Choi 4, Jisoo Shin 4, So Hyun Park 3, Myung-Wook Seon 1 2, Dakeun Lee 2 3, Jong-Ho Cha 4 5 6, You-Sun Kim 1 2 *
1Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
2Department of Biomedical Science, Graduate School of Ajou University, Suwon, 16499, Republic of Korea.
3Department of Pathology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
4Program in Biomedical Science and Engineering, Graduate school, Inha University, Incheon, 22212, Republic of Korea.
5Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.
6Biohybrid Systems Research Center, Inha University, Incheon, 22212, Republic of Korea.
2Department of Biomedical Science, Graduate School of Ajou University, Suwon, 16499, Republic of Korea.
3Department of Pathology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
4Program in Biomedical Science and Engineering, Graduate school, Inha University, Incheon, 22212, Republic of Korea.
5Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.
6Biohybrid Systems Research Center, Inha University, Incheon, 22212, Republic of Korea.
*Corresponding author: correspondence to You-Sun Kim
Abstract
Necroptosis plays a crucial role in the progression of various diseases and has gained substantial attention for its potential to activate antitumor immunity. However, the complex signaling networks that regulate necroptosis have made it challenging to fully understand its mechanisms and translate this knowledge into therapeutic applications. To address these challenges, an optogenetically activatable necroptosis system is developed that allows for precise spatiotemporal control of key necroptosis regulators, bypassing complex upstream signaling processes. The system, specifically featuring optoMLKL, demonstrates that it can rapidly assemble into functional higher-order “hotspots” within cellular membrane compartments, independent of RIPK3-mediated phosphorylation. Moreover, the functional module of optoMLKL significantly enhances innate immune responses by promoting the release of iDAMPs and cDAMPs, which are critical for initiating antitumor immunity. Furthermore, optoMLKL exhibits antitumor effects when activated in patient-derived pancreatic cancer organoids, highlighting its potential for clinical application. These findings will pave the way for innovative cancer therapies by leveraging optogenetic approaches to precisely control and enhance necroptosis.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-10)
- 국내 연구진
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