Cell Discovery Gao Zhaobing's research group collaborated to reveal the molecular mechanism by which MLKL channels perform cell death and neuroinflammation

MLKL (mixed-lineage kinase domain-like) is the executive protein of programmed necrosis, which plays a key role in development, immunity, inflammation and other physiological pathological processes, and is closely related to
the nervous system, immune system, tumor and other diseases.
However, the role of MLKL ion channels in pathological processes such as cell death and inflammation has not been clarified
.

Phosphatidylinositol diphosphate (PIP2) is distributed in cell membranes and a variety of cells, is an important cell signaling molecule, and is involved in a variety of physiological and pathological functions
.
Recently, the research team of Gao Zhaobing, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with Dr.
Wang Sheng of Fudan University, proved that PIP2 is an endogenous agonist of MLKL channels, and PIP2 enhances channel function and "ignites" MLKL-mediated procedural necrosis and inflammatory immune responses
。 The research results were published
in the international journal Cell Discovery under the title "Enhanced channel activity by PI(4,5)P2 ignites MLKL-related pathogenic processes".

In this study, the team investigated the regulatory effects of different membrane phospholipid components on MLKL channels, and found that PIP2 concentration increased, the current amplitude of MLKL channels increased, and the conductance increased, indicating that PIP2 participated in the regulation of the basic properties of
MLKL channels.
Through mutation scanning, the research team found key amino acid sites where
PIP2 regulates MLKL channels.
Subsequently, with the help of proteomics research, researchers found that in LPS-stimulated BV2 cells, PIP2 anabolic pathway and inflammatory response pathway were significantly increased, and the expression level of MLKL was also significantly increased
.
The research team then investigated the biological effects
of MLKL channels enhanced by PIP2.
Firstly, in the procedural necrosis model, PIP2 significantly enhances procedural necrosis and is positively correlated with channel function.
Second, in the neuroinflammatory model, it was found that MLKL channels directly mediate intracellular potassium depletion, while PIP2 with elevated cell membranes regulates the level of neuroinflammation (Figure 1).

This study provides new ideas
for understanding the physiopathological function of MLKL channel and targeting this channel to regulate cell death and inflammation-related diseases.

Associate researcher Xia Bingqing of Shanghai Institute of Materia Medica, is the first author of the study, and Dr.
Jingbo Xu of Fudan University is the co-first author
.
Researcher Gao Zhaobing and Dr.
Wang Sheng are co-corresponding authors
.
The Shanghai Institute of Materia Medica, the first completion
of this study.
This work has been supported
by the National Key R&D Program, Shanghai Daystar, the National Natural Science Foundation of China, and the Youth Innovation Promotion Association of the Chinese Academy of Sciences.

Original link:

Fig.
1 PIP2 enhances MLKL channel function to ignite programmed necrosis and inflammation

(Contributing department: Gao Zhaobing Research Group; Contributor: Xia Bingqing)