Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund’s adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.

Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The stability and catalytic function of DUSP6 are maintained through conjugation of small ubiquitin-like modifier-1 (SUMO1) and SUMO2/3 at lysine-234 (K234), which is disrupted during oxidation through transcriptional up-regulation of SUMO-deconjugating enzyme, SENP1, causing DUSP6 degradation by ubiquitin-proteasome. deSUMOylation underlies DUSP6 degradation, Drp1-S616 hyperphosphorylation, mitochondrial fragmentation, and apoptosis induced by H2O2 in cultured cells or brain ischemia/reperfusion in mice. Overexpression of DUSP6, but not the SUMOylation-deficient DUSP6K234R mutant, protected cells from apoptosis. Thus, DUSP6 exerts a cytoprotective role by directly dephosphorylating Drp1-S616, which is disrupted by deSUMOylation under oxidation.

No abstract

Supplemental Digital Content is Available in the Text.Peripheral nerve trauma-induced increase in E74-like factor 1 expression participates in neuropathic pain likely through upregulating matrix metallopeptidase 9 in injured dorsal root ganglion neurons.

Although the increase in the number of identified posttranslational modifications (PTMs) has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that different types of PTMs can crosstalk and act in concert to exert important regulatory mechanisms for protein function has not gained much attention. Here, we show that protein kinase Cδ (PKCδ) is SUMOylated at lysine 473 in its C‐terminal catalytic domain, and the SUMOylation increases PKCδ stability by repressing its ubiquitination. In addition, we uncover a functional interplay between the phosphorylation and SUMOylation of PKCδ, which can strengthen each other through recruiting SUMO E2/E3 ligases and the PKCδ kinase, respectively, to the PKCδ complexes. We identified PIAS2β as the SUMO E3 ligase of PKCδ. More importantly, by enhancing PKCδ protein stability and its phosphorylation through an interdependent interplay of the PTMs, the SUMOylation of PKCδ promotes apoptotic cell death induced by H2O2. We conclude that SUMOylation represents an important regulatory mechanism of PKCδ PTMs for the kinase's function in oxidative cell damage.