Formin-mediated nuclear actin assembly at androgen receptors promotes transcriptional droplet formation

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 identified 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 µm3 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 prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

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.…”

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.…”

“…Actin has been described as a component of chromatin remodeling complexes ( 36 ) as well as of RNA polymerases ( 37–39 ), implicating its involvement in transcriptional regulation. Conversely, dynamically polymerized actin, has only recently emerged in transcription control processes: in MRTF-A/SRF-mediated gene transcription ( 9 , 10 ), downstream of T- cell 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 ).…”

Actin associates with actively elongating genes and binds directly to the Cdk9 subunit of P-TEFb

“…Actin was linked to RNA polymerase function already almost 40 years ago (Scheer et al, 1984). Since then, several studies have demonstrated defects in transcription upon actin manipulations, whether with antibodies against actin (Hofmann et al, 2004; Miyamoto et al, 2011; Philimonenko et al, 2004), by altering nucleo-cytoplasmic actin shuttling (Dopie et al, 2012; Knerr et al, 2023; Le et al, 2016; Sokolova et al, 2018; Wei et al, 2020), by actin mutants that are either predominantly monomeric or filamentous (Almuzzaini et al, 2016; Huang et al, 2022; Knerr et al, 2023; Qi et al, 2011; Serebryannyy et al, 2016; Wei et al, 2020; Ye et al, 2008) or by using different actin-binding drugs (McDonald et al, 2006; Miyamoto et al, 2011; Wu et al, 2006; Ye et al, 2008). Nevertheless, the molecular mechanisms by which actin affects RNA polymerase function have remained rather unclear.…”