A novel peptide exerts potent immunosuppression by blocking the two-site interaction of NFAT with calcineurin.
J Biol Chem
; 295(9): 2760-2770, 2020 02 28.
Article
en En
| MEDLINE
| ID: mdl-31941790
ABSTRACT
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 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-induced asthma model. Our results suggest that pep3 is promising as an immunosuppressive agent and can be used in topical remedies.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
/
Unión Proteica
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Terapia de Inmunosupresión
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Calcineurina
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Factores de Transcripción NFATC
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
China