GPR107 Drives Psoriasis Inflammation by Blocking a Key Autophagy Protein's Destruction

Psoriasis affects roughly 2–3% of the global population and is characterized by hyperproliferating keratinocytes that sustain chronic skin inflammation through the secretion of chemokines, cytokines, and antimicrobial peptides. Understanding what drives this aberrant secretion is essential for developing better therapies. This study focuses on GPR107, an orphan GPCR whose role in skin disease was previously unknown, and reveals a complete molecular pathway connecting it to secretory autophagy in psoriatic keratinocytes.

The authors first established that GPR107 is robustly upregulated in psoriatic lesions using GEO datasets (GSE14905, GSE117468), immunohistochemistry of human biopsies, imiquimod (IMQ)-induced mouse models, and M5 cytokine-stimulated HaCaT and primary keratinocyte cell cultures. Critically, GPR107 expression was reduced after treatment with brodalumab, an anti-IL-17 receptor biologic, linking GPR107 levels to the psoriatic inflammatory milieu.

To assess functional relevance in vivo, the team generated keratinocyte-specific Gpr107 knockout mice (Krt14Cre-Gpr107f/f). Upon IMQ challenge, these mice displayed significantly lower PASI scores, reduced epidermal thickness, fewer Ki-67-positive proliferating keratinocytes, and attenuated expression of psoriasis markers compared with littermate controls. Complementary in vitro knockdown and overexpression experiments in HaCaT cells confirmed that GPR107 promotes keratinocyte proliferation and the secretion of inflammatory mediators including CCL20, CXCL1, CXCL8, and S100A7 via a secretory autophagy mechanism dependent on BECN1.

Mechanistically, internalized GPR107 recruits β-arrestin and activates ERK and NF-κB signaling. This pathway transcriptionally suppresses expression of the Cullin-3 (CUL3) E3 ubiquitin ligase. Reduced CUL3 leads to decreased K48-linked polyubiquitination of BECN1 specifically at lysine 206, preventing its proteasomal degradation. The resulting BECN1 stabilization enhances autophagosome formation and secretory autophagy flux, driving the release of leaderless inflammatory cargo. The authors validated each step—GPR107-β-arrestin interaction, ERK/NF-κB-mediated CUL3 suppression, K206-specific ubiquitination of BECN1—through co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, and rescue experiments.

These findings identify a previously unrecognized GPR107→β-arrestin/ERK/NF-κB→CUL3→BECN1→secretory autophagy axis as a central driver of psoriatic keratinocyte pathology. The axis represents a potentially druggable pathway, as each node offers a distinct intervention point. However, the work was conducted primarily in cell lines and mouse models, and the orphan nature of GPR107 means its endogenous ligand and precise upstream activators in psoriatic skin remain to be defined.