Ligand-dependent and -independent subcellular/subnuclear dynamics uncover new functional roles of ERRs in endocrine and metabolic regulation

Steroid hormone receptors (SRs) play pivotal roles in the fundamental biological functions related to reproduction, development, and homeostasis. They are also closely associated with various pathophysiologies, including hormone-dependent cancers, metabolic syndromes, and neuropsychiatric disorders. SRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. This superfamily also includes orphan nuclear receptors, such as estrogen-related receptors (ERRs) comprising three subtypes of α, β, and γ. Despite their high homology with estrogen receptors (ERs), ERRs cannot bind any endogenous steroid hormones and can activate gene transcription in a ligand-independent manner. Recently, ERRs have attracted considerable attention for their involvement in stem cell pluripotency, senescence, and other poorly understood biological processes. Although subcellular and subnuclear dynamics are crucial for SR function, how ERRs behave in living cells to activate or repress their target genes remains incompletely understood. We have investigated the behaviors of ERRs using fluorescent protein labeling, focusing on whether ERRs exhibit dynamic changes similar to SRs and whether these changes relate to their functional activity. In this review, we summarize findings from studies of molecular behavior, highlighting the coregulation of estrogen signaling by ERs and ERRs, the subnuclear movement of ERRs related to transcriptional repression, and the promotion of lactate metabolism by a novel lactate-responsive protein, LRPGC1, through interaction with ERRγ. We hope these insights contribute to elucidating fundamental biomedical processes and the pathological mechanisms linked to aberrant nuclear receptor signaling pathways.