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Saarinen M, Kotliar IB, Höffkes I, Branzell N, Bowin CF, Dahl L, Da Silva E, Glaros V, Abney A, Bendes A, Kreslavsky T, Schwenk JM, Sakmar TP, Svenningsson P
Sci Adv 12 (40) eaeg6567 [2026-10-02; online 2026-09-30]
The microprotein p11 (S100A10) is a ubiquitously expressed molecular scaffold that is known to be required for behavioral responses to certain antidepressants, presumably through its effect on G protein-coupled receptor (GPCR)-mediated signaling. Here, we demonstrate that p11 recruitment to GPCRs is promoted by an active receptor conformation. Furthermore, by mapping the GPCR-p11 interactome using a multiplexed suspension bead array (SBA) of 211 receptors, we identified more than two dozen high-confidence physical interactors across diverse GPCR signaling families. We define the functional significance of these interactions by focusing on a novel SBA screening hit, the protease-activated receptor 2 (PAR2). Transcriptomic fingerprinting and signaling assays in p11-knockout cells reveal that p11 acts as an amplifier of endogenous PAR2 signaling. PAR2 and p11 are specifically coexpressed in vivo in a subset of sensory neurons, and p11-deficient mice exhibit a blunted PAR2-mediated inflammatory response. Our results establish p11 as a widespread, activity-dependent modulator of GPCR-mediated signaling outcomes across diverse physiological processes.
CRISPR Functional Genomics [Service]
PubMed 42814836
DOI 10.1126/sciadv.aeg6567
Crossref 10.1126/sciadv.aeg6567