ZDHHC4-mediated S-palmitoylation of CD276 promotes breast tumorigenesis

Protein S-palmitoylation is catalyzed by a family of zinc finger Asp-His-His-Cys (ZDHHC) domain-containing palmitoyl acyltransferases, most of which are widely expressed in normal tissues and aberrantly increased in diverse malignant tumor tissues. However, the mechanisms of action of S-palmitoylation in tumor development are not fully understood. Here we profile interacting proteins of ZDHHC4, a member of the ZDHHC family, and further characterize the immune checkpoint CD276 as a substrate of ZDHHC4. ZDHHC4 mediates S-palmitoylation of CD276 at Cys488 and Cys496, which is reversed by palmitoyl-protein thioesterases (PPT1/2). Consequently, S-palmitoylation enhances the plasma membrane targeting of CD276 and increases its protein stability. Moreover, S-palmitoylation of CD276 promotes breast cancer cell proliferation and migration, and contributes to tumor growth in murine xenograft models. Thus, our study reveals an important molecular mechanism of S-palmitoylation in the regulation of CD276 function, highlighting the therapeutic potential of targeting ZDHHC4-CD276 signaling axis in breast cancer. DHHC4-mediated CD276 Spalmitoylation enhances the plasma membrane targeting of CD276 and increases its protein stability, contributing to tumor growth in murine xenograft models.