NR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis.

ABSTRACT: The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-respo

SUBMITTER: Haggerty NR 

PROVIDER: S-EPMC12596596 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature