Formin-mediated nuclear actin at androgen receptors promotes transcription

Abstract

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. Here we identi ed functional AIS-patient mutations in the formin and actin nucleator DAAM2. DAAM2 localized to the nucleus and colocalized with the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2-AR-droplets ranged from 0.02 to 0.06 µm 3 in size and associated with active RNA polymerase II. DAAM2 polymerizes actin directly at the AR to promote droplet fusion in a highly dynamic manner and actin polymerization is required for prostatespeci c antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II

“…Nuclear actin dynamics have emerged as a crucial regulator of nuclear functions including transcriptional control by driving androgen receptor condensate formation (14) or promoting RNA Pol II clustering in response to serum stimulation (11). In this study, we identify the inner nuclear membrane protein SUN2 as a key player in the rapid assembly of a highly dynamic nuclear actin filament network triggered by calcium signaling within seconds.…”

“…Conversely, dynamically polymerized actin, has only recently emerged in transcription control processes: in MRTF-A/SRF-mediated gene transcription (9, 10), downstream of Tcell receptor activation (40), or in response to androgen signaling (14), among others. It is well established that active RNA Pol II organizes into distinct nuclear foci often termed transcription factories (41).…”

“…Recently, dynamic actin filament assembly inside the nucleus has emerged as a more novel part of the nucleoskeleton promoting activation of serum response factor (SRF) (9,10), transcription (11), DNA repair (12,13), androgen signaling (14), as well as spatial chromatin reorganization (15). We could previously show that G-protein-coupled receptors (GPCRs) and nuclear calcium signaling mediates rapid formation of nuclear actin filaments for euchromatin formation through the actin regulator inverted formin 2 (INF2) (16).…”

Arp2/3 complex-dependent actin regulation protects the survival of tissue-resident mast cells

“…Since recent studies, mostly in non-immune cells, highlighted functional roles of the Arp2/3 complex in the nucleus (49,50), we explored whether nuclear Arp2/3 might contribute to the MC phenotype. To block nuclear Arp2/3 complex function, we employed a previously established experimental strategy involving the expression and shuttling of Arpin protein, a natural inhibitor of the Arp2/3 complex, to the nucleus (51). WT BMMCs were retrovirally transduced with mScarlet-Arpin-NLS or control mScarlet-NLS, which both localized to cell nuclei (Fig.…”

MolPhase: An Advanced Phase Separation Predictor and an Investigation of Phytobacterial Effector in Plant

“…Dissecting the biological functions of phase-separating proteins demands a multidisciplinary approach, intertwining both computational and experimental techniques. This entails localized quantitative molecule measurements, advanced molecular assembly imaging ranging from nanometer to mesoscale, and accurate assessment of functional molecule partitioning and stoichiometry (Case et al, 2019;Dine et al, 2018;Hubatsch et al, 2021;Kent et al, 2020;Knerr et al, 2023;Lee et al, 2023). To design experiments specifically for biomolecules in the context of their physiological or pathological pathways, MolPhase offers an accurate initial screen in a high-throughput manner, allowing for a systematic evaluation by integrating GO annotation, KEGG pathway enrichment analysis, or AlphaFold2-based structural prediction (Jumper et al, 2021).…”