Extracellular granzyme K links inflammatory signaling to nucleotide metabolism, driving epithelial hyperproliferation and reprogramming

Abstract Granzymes (Gzms) are a family of serine proteases that have been traditionally studied as cytotoxic mediators of lymphocyte-mediated target cell death. However, increasing evidence suggests that during inflammation Gzms can accumulate in the extracellular milieu and contribute to various pathologies depending on the Gzm. While much work has been done with respect to elucidating the extracellular impact of GzmB, less is understood for other Gzms. Recently, a role for extracellular GzmK was proposed for a number of pro-inflammatory and/or autoimmune conditions, including psoriasis. In order to further delineate a mechanistic role for GzmK in psoriasis, a transcriptomic approach was used to assess the impact of extracellular GzmK on cell signalling. Extracellular GzmK induced a temporally structured program of epithelial reprograming characterized by early activation of nucleotide biosynthesis, followed by proliferative commitment and induction of structural differentiation genes despite suppression of lipid biosynthesis. Mechanistically, GzmK selectively activated de novo purine biosynthesis at the level of the rate-limiting enzyme PPAT, and inhibition upstream of this pathway abrogated GzmK-driven hyperproliferation, identifying nucleotide availability as a limiting determinant of epithelial expansion. Integration with human psoriatic transcriptome, validation in patient tissues, and analysis in a murine model demonstrate that these programs are GzmK-dependent and relevant to human disease. Together, these findings define a non-canonical function of an immune protease linking inflammatory cues to epithelial metabolism and reprogramming.