G protein Gα_q subunits engage targets in the nucleus involved in chromatin remodeling and gene expression

Gα_q is a critical mediator of cell and tissue responses to G_q-coupled receptor stimulation. Canonically, active Gα_q regulates PLCβ and RhoGEFs. To identify novel Gα_q signaling partners, we performed a proximity labeling proteomic screen in HEK293A cells using TurboID-tagged Gα_q. Top Gα_q^(Q209L) enriched proteins included known Gα_q interactors (PLCβs, RhoGEFs, and GRK2), supporting the validity of this approach. Also highly enriched were several nuclear proteins including SMARCD3, a component of the SWI/SNF chromatin remodeling complex, and BCAS2, a component of the spliceosome. Luciferase complementation experiments show that Gα_q selectively interacts with BCAS2 and SMARCD3 in an activation-dependent manner, and pulldown experiments with purified components demonstrate direct interaction of Gα_q and SMARCD3. We also show that a small but significant portion of Gα_q is present in the nucleus, and this is increased following GPCR activation or introduction of an activating mutation. Proximity ligation assays indicate that Gα_q^(Q209L) engages SMARCD3 in the nucleus. These data suggest that Gα_q engages downstream targets in the nucleus and could therefore directly regulate nuclear processes.