Cathepsin L potentiates autoimmunity by inhibiting lysosome-mediated STING degradation.

The stimulator of interferon genes (STING) orchestrates type I interferon (IFN) production in response to cytosolic DNA and plays essential roles in antiviral defense and autoimmune pathogenesis. The stability of STING determines the activation intensity of the pathway. Therefore, identifying proteins that govern its homeostatic regulation is needed. Here, we uncover the lysosomal protease cathepsin L (CTSL) as a critical stabilizer of STING in cells. CTSL deficiency selectively impairs STING-induced IFN responses without compromising overall lysosomal digestive function. Mechanistically, CTSL interacts with AP1B1 to prevent AP1B1-mediated lysosomal degradation of STING, thereby enhancing IFN signaling. Furthermore, CTSL expression is elevated in cells from systemic lupus erythematosus (SLE) patients and positively correlates with disease activity. Together, our findings establish an important role of CTSL in innate immunity by regulating STING homeostasis.