LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea

Rosacea is a chronic inflammatory skin disorder linked to the antimicrobial peptide LL-37 and immune cells. STING, a key DNA-sensing adaptor, initiates innate immune responses, with excessive activation contributing to inflammation. This study investigates LAPTM5, a STING-interacting protein, and its role in rosacea. We observe elevated nuclear DNA fragmentation within the dermal lesions of rosacea patients and LL-37-induced rosacea-like mice. LAPTM5 and STING levels are upregulated in macrophages within rosacea lesions and LL-37-induced models, along with STING hyperactivation. LAPTM5 knockdown in macrophages reduces STING protein levels, signaling, and inflammatory responses under DMXAA and HT-DNA stimulation. LAPTM5 associates with STING and represses its K48- and K63-linked polyubiquitination, preventing proteasomal and lysosomal degradation, thereby maintaining STING stability at homeostasis and after activation. Both STING antagonist H-151 and LAPTM5 knockdown alleviate LL-37-induced rosacea-like phenotypes. These findings highlight LAPTM5 as a STING stabilizer, aggravating STING-driven inflammation in rosacea, offering insights for potential treatments.