Systematic identification of p11 as a signaling modulator across the GPCRome
) 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.
Authors
- Carl-Fredrik Bowin (ORCID: https://orcid.org/0000-0001-9090-9493)
- Annika Bendes (ORCID: https://orcid.org/0000-0001-9329-2353)
- Jochen M. Schwenk (ORCID: https://orcid.org/0000-0001-8141-8449)
- Per Svenningsson (ORCID: https://orcid.org/0000-0001-6727-3802)
- Alonso Abney (ORCID: https://orcid.org/0000-0002-0164-8314)
- Taras Kreslavsky (ORCID: https://orcid.org/0000-0002-6672-1914)
- Elisa Da Silva (ORCID: https://orcid.org/0009-0006-0105-2402)
- Vassilis Glaros (ORCID: https://orcid.org/0000-0001-6211-9515)
- Inga Höffkes
- Niclas Branzell (ORCID: https://orcid.org/0009-0009-3472-6903)
- Marcus Saarinen (ORCID: https://orcid.org/0000-0001-9019-8396)
- Thomas P. Sakmar (ORCID: https://orcid.org/0000-0002-2836-8953)
- Leo Dahl (ORCID: https://orcid.org/0000-0003-1492-3052)
- Ilana B. Kotliar (ORCID: https://orcid.org/0000-0001-9533-4828)
Institutions
- Karolinska University Hospital (SE)
- King's College London (GB)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Rockefeller University (US)
- KTH Royal Institute of Technology (SE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1126/sciadv.aeg6567
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health