PKCε SUMOylation Is Required for Mediating the Nociceptive Signaling of Inflammatory Pain

Despite the important roles of protein kinase Cε (PKCε) and transient receptor potential vanilloind 1 (TRPV1) in inflammatory hypersensitivity, how PKCε is involved in the regulation of thermal hyperalgesia is not fully understood. We report here that PKCε is SUMOylated at a C-terminal lysine residue (K534), which enhances the sensitivity of the TRPV1 channel. We demonstrate that PKCε phosphorylation promotes its SUMOylation, which in turn regulates the phosphorylation level of TRPV1 serine 800 residue via controlling the binding of PKCε and TRPV1 and increased PKCε kinase activity. More importantly, the reduced ability of PKCε knockdown mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 4/5 dorsal root ganglia neurons of wild-type PKCε, but not the SUMOylation-deficient PKCε mutant. Therefore, the SUMOylation of PKCε potentiates inflammatory thermal hyperalgesia through stabilizing the interaction with TRPV1 to enhance its function by phosphorylation.