Signal peptide-independent secretion of keratin-19 by pancreatic cancer cells

T cells exclusion precludes checkpoint inhibition efficacy in pancreatic ductal adenocarcinoma (PDA) and is mediated by the interaction between T cell CXCR4, and its ligand CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion is essential to this proccess but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using ER-restricted TurboID systems and a split-GFP assay, we demonstrate that KRT19 enters the ER via its head domain. In vivo, tumors formed with ER-TurboID cells contain biotinylated KRT19. Additionally, KRT19 is shown to interact with the signal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. Although keratin-8 (KRT8) co-localizes with KRT19 on the surface of PDA cells, KRT8 does not enter the ER. However, both keratins are externalized via secretory autophagy. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to protect against immune attack.