Abstract
TNFα is a highly pleiotropic cytokine inducing inflammatory signaling pathways. It is initially presented on plasma membrane of cells (mTNFα), and also exists in a soluble variant (sTNFα) after cleavage. The ligand is shared by two structurally similar receptors, TNFR1 and TNFR2. Interestingly, while sTNFα preferentially stimulates TNFR1, TNFR2 signaling can only be activated by mTNFα. How can two similar receptors respond to the same ligand in such a different way? We employed computational simulations in multiple scales to address this question. We found that both mTNFα and sTNFα can trigger the clustering of TNFR1. The size of clusters induced by sTNFα is constantly larger than the clusters induced by mTNFα. The systems of TNFR2, on the other hand, show very different behaviors. Only when the interactions between TNFR2 are very weak, mTNFα can trigger the receptors to form very large clusters. Given the same weak binding affinity, only small oligomers were obtained in the system of sTNFα. Considering that TNF-mediated signaling is modulated by the ligand-induced clustering of receptors on cell surface, our study provided the mechanistic foundation to the phenomenon that different isoforms of the ligand can lead to highly distinctive signaling patterns for its receptors.
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Acknowledgements
This work was supported by the National Institutes of Health under Grant Numbers R01GM120238 and R01GM122804. The work is also partially supported by a start-up grant from Albert Einstein College of Medicine. Computational support was provided by Albert Einstein College of Medicine High Performance Computing Center and by the National Science Foundation through the Extreme Science and Engineering Discovery Environment (XSEDE) under Grant Number TG-MCB200014.
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ZS and YW designed research; ZS and YW performed research; ZS and YW analyzed data; ZS and YW wrote the paper.
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Su, Z., Wu, Y. How does the same ligand activate signaling of different receptors in TNFR superfamily: a computational study. J. Cell Commun. Signal. 17, 657–671 (2023). https://doi.org/10.1007/s12079-022-00701-2
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DOI: https://doi.org/10.1007/s12079-022-00701-2