RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells.
JMG, Animals, Mice, Carrier Proteins, GTP-Binding Protein alpha Subunits, Gi-Go, GTPase-Activating Proteins, Guanine Nucleotide Exchange Factors, Guanosine Diphosphate, Heterotrimeric GTP-Binding Proteins, RGS Proteins, Stereocilia
Sci Adv. 2022;8(42):eabq2826
This work was supported by a JAX Scholar postdoctoral fellowship (to A.A.) and National Institute on Deafness and Other Communication Disorders grants R01DC015242 and R01DC018304 (to B.T.).
Inhibitory G proteins (GNAI/Gα(i)) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are deaf. GPSM2 and RGS12 share GoLoco motifs that stabilize GNAI(GDP), and GPSM2 outcompetes RGS12 to bind GNAI. Our results suggest that polarized GEF/GAP junctional activity might dissociate heterotrimeric G proteins, generating free GNAI(GDP) for GPSM2 at the adjacent apical membrane. GPSM2-GNAI(GDP), in turn, imparts asymmetry to the forming stereocilia to enable sensory function in hair cells.
RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells. Sci Adv. 2022;8(42):eabq2826
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