Title : Nuclear tug-of-war: Competitive VDR/RXR–NFAT1 regulation of coronin-1 governs mycobacterial survival
Abstract:
Coronin-1 (Cor1), also known as p57 or TACO (for Tryptophan Aspartate containing Coat protein), a highly conserved WD-repeat protein enriched in immune cells, orchestrates host–pathogen interactions and immune signalling; yet the molecular circuitry controlling its transcription remains poorly characterized. Coronin-1 was initially identified as a host determinant that, in resting macrophages, inhibits phagosome–lysosome fusion following mycobacterial uptake. Upon infection, Coronin-1 is selectively recruited to and retained on mycobacteria-containing phagosomal membranes, where it delays phagosomal maturation by restricting the recruitment of the phagosome maturation machinery, thereby promoting intracellular survival of pathogenic mycobacteria. Given the central role of macrophages at the interface of innate and adaptive immunity, where they integrate pathogen sensing, antigen processing and presentation, and antimicrobial effector programs, elucidating the regulatory mechanisms governing Cor1 expression is essential for understanding host pathways that influence pathogen persistence. We sought to demonstrate that Vitamin D3 (VitD3) and retinoic acid (RA) robustly repress Cor1 transcription via competitive promoter occupancy, whereby ligand-activated VDR/RXR heterodimers displace NFAT1 from a critical regulatory site within the Cor1 promoter. Chromatin immunoprecipitation and luciferase reporter analyses identify NFAT1 as the dominant transcriptional activator of Cor1 in THP-1 macrophages. Consistent with the role of NFAT1 as a key regulator of macrophage function, particularly in modulating immune responses and cytokine production via the Calcineurin-NFAT1 signalling pathway, inhibition of this pathway resulted in a marked reduction in Cor1 protein levels, as confirmed by immunoblotting and immunofluorescence analyses. Strikingly, perturbation of the calcineurin–NFAT1 axis sharply reduced Cor1 levels, markedly enhancing macrophage-mediated mycobacterial clearance. This work uncovers previously unrecognized transcriptional circuitry for Cor1 regulation and positions the calcineurin–NFAT1 pathway as a compelling therapeutic target for immune modulation and host-directed interventions against infectious disease.
Keywords: Coronin-1 (Cor1), VDR/RXR, NFAT1, Calcineurin, Mycobacterial clearance
