A casein-derived peptide exerted immunomodulatory effects by targeting protein phosphatase 1-catalytic subunit alpha: a potential alternative to combat infections

Antibiotic resistance is a growing global threat to the effective treatment of bacterial infections, therefore, novel therapeutic alternatives need to be developed urgently. We recently reported that BCCY-1, a peptide derived from human β-casein, displayed regulatory effects on innate immune responses. The aim of this study was to identify the cellular target and unveil the molecular mechanism of BCCY-1 that mediated these effects. Here, we demonstrated that the chemokine induction activity of peptide BCCY-1 relied on the integrity of its amino acid sequence which was attributed to its binding affinity for protein phosphatase 1 catalytic subunit alpha (PP1A). BCCY-1 could inhibit the PP1A-mediated dephosphorylation and thus promote activation of the NF-κB and MAPK signaling pathways, as well as downstream chemokine expression in THP-1 cells, both of which were significantly reversed by PP1 activation. Moreover, tautomycin, a chemical inhibitor of PP1A, mimicked the effects of BCCY-1 on the immune response by monocytes. BCCY-1 as well as tautomycin enhanced the recruitment of innate myeloid cells to the site of infection, eventually contributing to bacterial clearance <i>in vivo</i>. This study would broaden the understanding of milk-derived immunomodulatory peptides in preventing and treating infectious diseases.