GPR107 promotes autophagy secretion in psoriatic keratinocytes by inhibiting BECN1 K48-linked ubiquitination.

Psoriasis is a chronic inflammatory skin disease driven by excessive proliferation and aberrant differentiation of keratinocytes. Autophagy-based unconventional secretory pathway (secretory autophagy) plays key roles in regulating cell proliferation and autosecretion in psoriatic keratinocytes; however, their upstream regulators remain poorly defined. The orphan G protein-coupled receptor 107 (GPR107) mediates signal transduction via clathrin-dependent endocytosis. Here, we report that upregulation of GPR107 in psoriatic keratinocytes promotes both cell proliferation and the secretion of chemokines and antimicrobial peptides through BECN1-dependent autophagy. Mechanistically, internalized GPR107 activates the β-arrestin/ERK/NF-κB pathway. This activation not only drives the direct transcription of inflammatory factors but also negatively regulates the expression of E3-ubiquitin ligase CUL3. The reduction of CUL3 decreases K48-linked ubiquitination at K206 of BECN1, preventing its proteasomal degradation. Stabilization of BECN1 facilitates secretory autophagy in psoriatic keratinocytes, further enhancing their proliferation and inflammatory responses. These findings highlight a novel function of GPR107 in psoriasis, and suggest that the integrated β-arrestin/ERK/NF-κB/CUL3/BECN1 axis may serve as a potential therapeutic target for this disease.