Compartmentalization of casein kinase 1 γ CSNK1G controls the intracellular trafficking of ceramide

Casein kinase 1 gamma (CK1G) is involved in the regulation of various cellular functions. For instance, the ceramide transport protein (CERT), which delivers ceramide to the Golgi apparatus for the synthesis of sphingomyelin (SM), is inactivated when it receives multiple phosphorylation by CK1G. Using human genome-wide gene disruption screening with an SM-binding cytolysin, we found that loss of the C-terminal region of CK1G3 rendered the kinase hyperactive in cells. Deletion of the C-terminal 20 amino acids or mutation of cysteine residues expected to be palmitoylated sites redistributed CK1G3 from cytoplasmic punctate compartments to the nucleocytoplasm. Wild-type CK1G3 exhibited a similar redistribution in the presence of 2-bromopalmitate, a protein palmitoylation inhibitor. Expression of C-terminal mutated CK1G1/2/3 similarly induced the multiple phosphorylation of the CERT SRM, thereby downregulating de novo SM synthesis. These findings revealed that CK1Gs are regulated by a compartmentalization-based mechanism to access substrates present in specific intracellular organelles.

Automated summary

Casein kinase 1 gamma (CK1G) plays a role in regulating cellular functions and has been found to inactivate the ceramide transport protein (CERT) through phosphorylation. In this study, it was discovered that loss of the C-terminal region of CK1G3 led to hyperactivation of the kinase and redistribution within the cell. These findings suggest that CK1Gs are regulated through compartmentalization to access specific intracellular organelles.