VDR/RXR antagonizes calcineurin-activated NFAT1, an essential regulator of Coronin-1A expression and Mycobacterial persistence.

Abstract

Coronin-1A (CORO1A), a conserved WD-repeat protein enriched in immune cells, plays a pivotal role in host-pathogen interactions and immune regulation, yet the mechanisms controlling its expression have remained elusive. We identify Vitamin D3 (VitD3) and Retinoic acid (RA) as potent repressors of CORO1A transcription via a novel competitive displacement mechanism, wherein soluble VDR/RXR heterodimers outcompete NFAT1 at its binding site on the CORO1A promoter. Luciferase reporter assays, Chromatin immunoprecipitation and Electrophoretic Mobility Shift Assays pinpoint NFAT1 as the dominant transcriptional driver of CORO1A in the myeloid lineage, with NFAT1/NFAT2 jointly controlling its expression in lymphoid cells. Strikingly, perturbation of the calcineurin-NFAT1 axis sharply reduces CORO1A levels, markedly enhancing macrophage-mediated mycobacterial clearance. This work uncovers previously unrecognized lineage-specific transcriptional circuitry for CORO1A regulation and positions the calcineurin-NFAT1 pathway as a compelling therapeutic target for immune modulation and host-directed interventions against infectious disease.