Wntless degradation mediated by CaMKII inhibition drives endoplasmic reticulum stress and apoptosis.

Noncanonical Wnt signaling stimulates calcium release and subsequent activation of calcium/calmodulin-dependent protein kinase 2 (CaMKII). We find that CaMKII inhibition decreases Wnt synthesis and identify the downregulation of Wntless (WLS) as the basis for this decrease. WLS transports palmitoylated Wnts to the cell surface, and in the absence of Wnts, it undergoes endoplasmic reticulum (ER)-associated degradation (ERAD). CaMKII inhibition increases proteasome-dependent WLS degradation, which can be suppressed by Wnt overexpression, indicating that CaMKII contributes to ER handling of unliganded WLS and prevention of ERAD. CaMKII inhibition also causes a loss of calnexin, an ER stress response through the activation of PERK, and apoptosis in cells expressing high levels of WLS. Moreover, these effects can be prevented by WLS knockdown. The findings reveal a previously unidentified role for CaMKII in supporting ER chaperone functions. They further show that high levels of unliganded WLS could be a potent driver of ER stress in the presence of CaMKII inhibitors, which may have efficacy in tumors expressing high levels of WLS.