Human PRSS8 functions as a targetable, endogenous TGFBR3 sheddase via the novel cholesterol-PRSS8-TGF-β axis.

Many cancers display dysregulation of the TGF-β pathway, which can produce a myriad of oncogenic phenotypes including evasion of the immune system, epithelial to mesenchymal transition, metastasis, and angiogenesis. As such, this pathway has been of much interest when trying to design new therapeutic options. Unfortunately, these attempts to inhibit TGF-β have had very limited success, likely because of the critical roles that TGF-β plays in the normal tissues of the body. For this reason, the work here aimed to more fully understand the regulation of TGF-β signaling with a long-term goal of restoring normal TGF-β signaling by manipulating these regulatory events. The co-receptor TGFBR3 can promote TGF-β signaling when bound to the cell surface. However, this co-receptor can also be shed from the membrane and inhibit signaling. The enzyme responsible for TGFBR3 shedding and the regulatory mechanisms controlling this process remain poorly characterized. Here, PRSS8 was identified to be an endogenous sheddase of TGFBR3, and the expression of PRSS8 had functional impacts on phenotypes mediated by TGF-β signaling. Furthermore, PRSS8, and therefore TGF-β signaling, can be regulated by cholesterol homeostasis pathways. This establishes for the first time a cholesterol-PRSS8-TGF-β signaling axis that could provide novel therapeutic options for cancers experiencing dysregulated TGF-β signaling.