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Dr. Xiaodong Wang’s lab discovered two mammalian membrane transporting pathways that negatively regulate necroptosis

Publication Date:2019/06/06

On May 28th,2019---Dr Xiaodong Wang’s lab has published a cover story on the journal of Science Signalingthat is titled “Flotillin-mediated endocytosis and ALIX–syntenin-1–mediated exocytosis protect the cell membrane from damage caused by necroptosis”. In the article, they reported the discovery of two mammalian membrane transporting pathways that negatively regulate necroptosis.

Programed necrosis (necroptosis) is a type of mammalian specific cell death form. In the past decade, necroptosis has been the main research topic in Dr Wang’s lab. They have discovered the key signal transducing and executing molecules of necroptosis—RIP3 kinase and its substrate MLKL protein. They demonstrated that once MLKL is phosphorylated by RIP3 at particular sites, the phosphorylated MLKL protein would then translocate from cytosol to the cell membrane, on which MLKL carries out its membrane-disrupting activity and causes cell death. However, in certain tissues, phosphorylated MLKL was seen on cell membrane, yet the cells were still alive.


Fig.1 Flotillin-mediated endocytosis and ESCRT-mediated exocytosis independently repair cell membrane that’s damaged by p-MLKL during necroptosis

Intrigued by such phenomenon, Dr. Wang’s lab carried decided to study what happens to p-MLKL once it has targeted the cell membrane. The research took many years and twists, eventually Dr. Weiliang Fan, with the help from team members, identified a complexed membrane repairing system that could counteract the MLKL-dependent membrane damage during necroptosis. It has become clear now, once MLKL was phosphorylated, it would translocate onto special membrane microdomains termed lipid rafts through the interaction with Flotillin1/2 proteins. The flotillin proteins then mediated a special endocytosis pathway, which carried the p-MLKL into lysosomes, where p-MLKL were degraded, and necroptosis was prevented. Besides the flotillin mediated endocytosis, p-MLKL also activated an ALIX-Syntenin-1 mediated, ESCRT dependent exocytosis pathway, by which the p-MLKL was expelled from the cell membrane on the form of exosomes. These two negative regulatory pathways of necroptosis acted independently and were utilized to different extend among cells. The activated MLKL protein had to overcome these two negative regulations before cell death could occur.

(Fig. 2 p-MLKL signal was highly accumulated in the hippocampal neuron in Alzheimer’s patients’ autopsy samples)

Current work also discovered the existence of polymorphism on the MLKL-binding region of Flotilin-1 protein. Some of which would block the Flotilllin-1 mediated MLKL degradation. This pathway may also play key roles in the pathology of Alzheimer’s disease. In current work, in corroboration with Dr Jing ZhangDepartment of Pathology, University of Washington School of Medicine, Seattle, WADepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing and Ms. Hua Wang (Department of Pathology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Pathology, Peking University Third Hospital, Beijing), Dr. Wang’s lab discovered that hippocampal neurons accumulated significantly more p-MLKL signal in the Alzheimer’s patients’ autopsy sample than control patient at similar age. Majority of these p-MLKL signals were in colocalization with Flotillin within the cytosol of these neurons.

Dr.Weiliang Fan, a postdoctoral fellow in Dr. Wang’s lab is the leading author of the study. Other authors include Dr. Jia Guo, Beichen Gao (former technician, now PhD student), Wenbin Zhang (PhD student), Liucong Ling (former technician), Tao Xu (former technician), Chenjie Pan (Now postdoctoral fellow at Harvard medical school), Lin Li, Dr.She Chen, Dr.Jing Zhang (Professor at Department of Pathology, University of Washington School of Medicine, Seattle, WADepartment of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing), Hua Wang (Doctor at Department of Pathology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Pathology, Peking University Third Hospital, Beijing). Dr.Xiaodong Wang is the corresponding author. Great help has been given by Yue Sun and Dr. Cheng Zhan from the microscopic facility, Dr. Zhaodi Jiang from the electron microscopic facility at the National Institute of Biological Sciences, Beijing. This work was supported by National Basic Science 973 grant no. 2010CB835400 from the Chinese Ministry of Science and Technology. W.F. was supported by an Amgen-China postdoctoral fellowship from 2014 to 2018.