Lipids are the major structural components of cell membrane but they also carry important signaling function. Anionic phospholipids in the plasma membrane can interact with proteins that have polybasic stretchs and thus can specifically regulate protein function, such as receptor activation and channel opening. But, how this type of ionic protein-lipid interaction is regulated in cells is still unknown. Now, researchers from Chinese Academy of Sciences and Tsinghua University reported that metal ion Ca2+ can bind directly to anionic phospholipids and amplify T-cell receptor-CD3 complex (TCR) activation signal.
TCR is one of the most complicated and sensitive receptors in mammalian cells, which is expressed primarily on the surface of T lymphocytes. It can detect even one single antigen molecule and then initiate T cell’s immune response against invading pathogens. However, the mechanism of TCR triggering is still largely unknown. The first signaling event of TCR triggering is the tyrosine phosphorylation of CD3 chains. Previous work by Prof. XU Chenqi showed that ionic lipid-protein interactions between the positively charged CD3 cytoplasmic domains (CD3CD) and negatively charged phospholipids in the plasma membrane could lock the critical tyrosine residues in cell membrane and prevent TCR from spontaneous phosphorylation in resting T lymphocytes. This time, his group from Shanghai Institute of Biochemistry and Cell Biology, CAS and his collaborators told the second part of the whole story.
By using high resolution imaging technologies, they found that TCR-proximal Ca2+ concentration was higher than the global Ca2+ concentration in activated T-cells. These local Ca2+ ions would directly bind to the negatively-charged phosphate group of phospholipids and thus disrupt CD3-lipid interaction and lead to the solvent exposure of the key tyrosines. Under physiological triggering condition, Ca2+ indeed could facilitate CD3 phosphorylation and amplify the weak initial TCR activating signal to a higher level. This positive feedback regulation of Ca2+ could largely increase the sensitivity of T cells to foreign antigens. Moreover, their study provides a novel regulatory mechanism that Ca2+ could directly manipulate lipids to change protein function, which potentially could be extened to study other signaling pathways.
This work, published on Nature, was a collaboration with Dr. WANG Junfeng’s lab from High Magnetic Field laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Dr. LIU Wanli’s lab from Tsinghua University. It was funded by Ministry of Science and Technology, National Science Foundation of China, Chinese Academy of Sciences and Shanghai Municipal Commission for Science and Technology.
AUTHOR CONTACT:
Dr. XU Chenqi
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
Phone: 86-21-54921318;
E-mail: cqxu@sibcb.ac.cn
Schematic illustration of Ca2+-induced TCR signaling amplification model (image provided by Dr. XU Chenqi’s lab)
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