Researchers from Xiamen University Academy of Sciences, Zhejiang University Academy of Sciences and other departments have further revealed the key mechanism of cell necrosis: the mechanism of action of protein kinase RIP3-the interaction between RIP3-MLKL during the formation of necrosomes Played a key role, which has been confirmed in humans and mice. Related results were published in JBC Magazine. The author is Professor Han Jiahuai of Xiamen University Academy of Sciences. Professor Han Jiahuai's research focuses on intracellular signal transmission in the innate immune system. Research directions include: 1. Molecular mechanism of inflammatory response and immune diseases; 2. The relationship between stress (such as radiation, many chemical carcinogens, pathogen infections, inflammatory factors and gene mutations, etc.) and cancer development and other diseases. The cell death mechanism has always been one of the core hotspots in biomedical research. There are currently three main types of cell death recognized, the first is "necrosis", the second is "apoptosis", and the third is "autophagy" . Both apoptosis and autophagy require energy and synthesis of new proteins. It is an active process of cell self-regulation, so it is also known as "programmed death." For a long time, people's understanding of apoptosis has been relatively clear, and cell necrosis The molecular mechanism and how cell apoptosis and cell necrosis are converted into each other in the scientific community is still a mystery. After six years of research, Professor Han's research group found that a protein kinase called RIP3, which exists in the human body, can regulate the energy metabolism and convert tumor necrosis factor-induced apoptosis into cell necrosis. In other words, this protein kinase is a molecular "switch" that converts between apoptosis and necrosis. It can affect the choice of different death methods for cells by regulating energy metabolism. Studies have shown that phosphorylation at the S227 position of human RIP3 (hRIP3) can promote its interaction with hMLKL in the necrosome pathway-when cell necrosis is induced, RIP1 and RIP3 combine to form a signal called "necrosome" Complex. In this article, Professor Han et al. Found that TNF can induce the phosphorylation of T231 and S232 in RIP3 (mRIP3) in mice, and this phosphorylation process is also an essential factor for mRIP3 and mMLKL to go away from each other. S232 in mRIP3 corresponds to S227 hRIP3 in hRIP3, but T231 is not conservative and is not found in humans. Although human and mouse cell necrosis processes require RIP3-MLKL interaction, experiments have shown that hRIP3 cannot interact with mMLKL, and mRIP3 cannot bind hMLKL. This species specificity mainly depends on the sequence of the phosphorylation sites of hRIP3 and mRIP3, and the sequence around the phosphorylation sites. It seems that the interaction between RIP3-MLKL has been selected as an evolutionary conservative mechanism that mediates cell necrosis, although in different organisms, basic mechanism interactions of different structures and mechanisms have simultaneously emerged. In addition, the researchers further found that the interaction between RIP3 and MLKL can prevent large-scale abnormal aggregation of RIP3, so it is also significant for necrosomes, an amyloid signaling complex. Studies have also shown that translocation of necrosomes to the mitochondrial-associated membrane (MAM) also requires the interaction of RIP3 and MLKL. These research data prove the importance of the interaction between RIP3-MLKL in the formation of necrosomes, thus pointing out that the MAM translocation of necrosomes is a necessary part of the process of cell necrosis. In 2009, Professor Han Jiahuai completed a key achievement in the field of cell necrosis within one year of returning home. They found that in NIH3T3 cells, protein kinase RIP3 is an important molecular switch that initiates apoptosis or cell necrosis, and In other cells, the cell necrosis procedure also requires the participation of RIP3. RIP3 does not affect RIP1-mediated apoptosis, but it does affect RIP1-mediated cell necrosis. RIP3 can enhance cell necrosis through the caspase inhibitor zVAD. RIP3 regulates the production of TNF-mediated reactive oxygen species by activating the activities of key metabolic enzymes, and reactive oxygen species can promote RIP3-induced cell necrosis. These results indicate that the regulation of stress energy metabolism produced by cells after being stimulated by death is of great significance for the cells to choose self-apoptosis and cell necrosis. RIP3 is a biological switch that regulates apoptosis or cell necrosis. GlazeKing Ceramics TechnologyCo.,Ltd. , http://www.maglazekingceramics.com
Latest research results: key factors of cell necrosis