GPR107 promotes secretory autophagy and inflammation in psoriatic keratinocytes by stabilizing BECN1 via the β-arrestin/ERK/NF-κB/CUL3 axis

Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation and aberrant differentiation. A key pathway implicated in this pathology is the autophagy-based unconventional secretory pathway, or secretory autophagy, which regulates cell proliferation and autosecretion in psoriatic keratinocytes. However, the upstream regulators of this crucial pathway remain largely undefined. Understanding these regulators could unveil novel therapeutic targets to modulate keratinocyte behavior and mitigate the inflammatory cascade in psoriasis.

Researchers investigated the role of the orphan G protein-coupled receptor 107 (GPR107) in psoriatic keratinocytes. They observed the upregulation of GPR107 in these cells and subsequently explored its impact on cell proliferation and the secretion of inflammatory mediators. The study focused on dissecting the mechanistic cascade by which GPR107 exerts its effects, specifically examining its interaction with the β-arrestin/ERK/NF-κB pathway and its downstream influence on BECN1-dependent autophagy. This involved characterizing the molecular events linking GPR107 activation to changes in BECN1 stability and secretory autophagy.

The study found that GPR107 is upregulated in psoriatic keratinocytes, promoting both cell proliferation and the secretion of chemokines and antimicrobial peptides. This effect was shown to be mediated through BECN1-dependent autophagy. Mechanistically, internalized GPR107 activates the β-arrestin/ERK/NF-κB pathway. This activation serves a dual role: it directly drives the transcription of inflammatory factors and, crucially, negatively regulates the expression of the E3-ubiquitin ligase CUL3. The reduction of CUL3 activity leads to a decrease in K48-linked ubiquitination at K206 of BECN1. This specific ubiquitination event is critical for BECN1's proteasomal degradation. > Stabilization of BECN1 due to reduced K48-linked ubiquitination facilitates secretory autophagy in psoriatic keratinocytes, which further enhances their proliferation and inflammatory responses. These findings establish a novel GPR107-mediated signaling axis that directly impacts psoriasis pathogenesis.