Formin-mediated nuclear actin at androgen receptors promotes transcription.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic, and behavioral functions, and is involved in various conditions including androgen-insensitivity-syndrome (AIS) or prostate cancer 1. Here we identified functional AIS-patient mutations in the formin and actin nucleator DAAM2. DAAM2 was enriched in the nucleus, where its localization correlated with that of the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2-AR-droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerized actin directly at the AR to promote droplet coalescence in a highly dynamic manner and nuclear actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

Nature. 2023 Mar 27 [Epub ahead of print]

Julian Knerr, Ralf Werner, Carsten Schwan, Hong Wang, Peter Gebhardt, Helga Grötsch, Almuth Caliebe, Malte Spielmann, Paul-Martin Holterhus, Robert Grosse, Nadine C Hornig

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany., Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany., Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany., Department of Paediatrics, Division of Paediatric Endocrinology and Diabetes, University Hospital of Schleswig-Holstein, Kiel, Germany., Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany. ., Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany. .