Alternate trafficking of cathepsin L in dermal fibroblasts induced by UVA radiation

UVA radiation is increasingly used to treat fibrotic skin disorders. However, the mechanisms underlying the therapeutic effects of UVA for these disorders are only partially understood. Cathepsin L is a lysosomal cysteine protease, which has been shown to degrade various matrix proteins thus contributing to extracellular remodeling. Therefore, we investigated whether UVA irradiation regulates the expression and release of cathepsin L in human dermal fibroblasts. No alterations were found after single irradiation; however, a significantly increased extracellular release of cathepsin L was observed after repeated irradiation up to four times. The transcript levels of cathepsin L were elevated after repetitive irradiation, leading to increased amounts of total cathepsin L protein. Furthermore, higher amounts of extracellular cathepsin L were associated with a significant reduction of intracellular processed cathepsin L and an accumulation of unprocessed procathepsin L. The use of specific inhibitors elucidated mannose phosphate-independent sorting pathways of cathepsin L leading to enhanced secretion and reduced intracellular processing. This is the first study which demonstrates that alternate trafficking mechanisms mediate the extracellular release of a cysteine protease induced by repetitive UVA irradiation.