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A novel peptide exerts potent immunosuppression by blocking the two-site interaction of NFAT with calcineurin
Journal of Biological Chemistry ( IF 4.106 ) Pub Date : 2020-01-15 , DOI: 10.1074/jbc.ra119.010254
Lu Wang, Na Cheng, Ping Wang, Jing Li, Anna Jia, Wenying Li, Nan Zhang, Yanxia Yin, Li Tong, Qun Wei, Guangwei Liu, Zhimei Li, Jing Luo

The calcineurin/nuclear factor of activated T cell (CN/NFAT) signaling pathway plays a critical role in the immune response. Therefore, inhibition of the CN/NFAT pathway is an important target for inflammatory disease. The conserved PxIxIT and LxVP motifs of CN substrates and targeting proteins have been recognized. Based on the affinity ability and inhibitory effect of these docking sequences on CN, we designed a bioactive peptide (named pep3) against the CN/NFAT interaction, which has two binding sites derived from the RCAN1-PxIxIT motif and the NFATc1-LxVP motif. The shortest linker between the two binding sites in pep3 is derived from A238L, a physiological binding partner of CN. Microscale thermophoresis (MST) revealed that pep3 has two docking sites on CN. Pep3 also has the most potent inhibitory effect on CN. It is suggested that pep3 contains an NFATc1-LxVP-substrate recognition motif and RCAN1-PxIxIT-mediated anchoring to CN. Expression of this peptide significantly suppresses CN/NFAT signaling. Cell-permeable 11-arginine-modified pep3 (11R-pep3) blocks the NFAT downstream signaling pathway. Intranasal administration of the 11R-pep3 peptide inhibits airway inflammation in an ovalbumin (OVA)-induced asthma model. Our results suggest that pep3 is promising as an immunosuppressive agent and can be used in topical remedies.
更新日期:2020-01-16

 

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