DeSUMOylation of MKK7 kinase by the SUMO2/3 protease SENP3 potentiates lipopolysaccharide-induced inflammatory signaling in macrophages

Abstract

Protein SUMOylation has been reported to play a role in innate immune response, but the enzymes, substrates, and consequences of the specific inflammatory signaling events are largely unknown. Reactive oxygen species (ROS) are abundantly produced during macrophage activation and required for Toll-like receptor 4 (TLR4)–mediated inflammatory signaling. Previously, we demonstrated that SENP3 is a redox-sensitive SUMO2/3 protease. To explore any links between reversible SUMOylation and ROS-related inflammatory signaling in macrophage activation, we generated mice with Senp3 conditional knock-out in myeloid cells. In bacterial lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models, we found that SENP3 deficiency markedly compromises the activation of TLR4 inflammatory signaling and the production of proinflammatory cytokines in macrophages exposed to LPS. Moreover, Senp3 conditional knock-out mice were significantly less susceptible to septic shock. Of note, SENP3 deficiency was associated with impairment in JNK phosphorylation. We found that MKK7, which selectively phosphorylates JNK, is a SENP3 substrate and that SENP3-mediated deSUMOylation of MKK7 may favor its binding to JNK. Importantly, ROS-dependent SENP3 accumulation and MKK7 deSUMOylation rapidly occurred after LPS stimulation. In conclusion, our findings indicate that SENP3 potentiates LPS-induced TLR4 signaling via deSUMOylation of MKK7 leading to enhancement in JNK phosphorylation and the downstream events. Therefore this work provides novel mechanistic insights into redox regulation of innate immune responses.

Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy

“…These enzymes include an E1 SUMO-activating enzyme, the E2-conjugating enzyme Ubc9, and an E3 ligase, such as the PIAS family proteins, RanBP2, and Pc2, which facilitate the transfer of SUMO from Ubc9 to specific target proteins ( 16 ). Previous data suggested that the conjugation of SUMO2 and SUMO3 is predominantly induced as an intracellular protective response to cellular stresses, such as hypoxia and inflammatory stimuli ( 17 ). There is also a series of reports showing a neuroprotective role of SUMOylation in brain lesions caused by ischemia-reperfusion injury ( 18 ).…”

Redox-sensitive enzyme SENP3 mediates vascular remodeling via de-SUMOylation of β-catenin and regulation of its stability

“…Because SENP3 −/− mutation causes embryonic lethality [28] , SENP3 +/− mice were generated. To further define the in vivo role of SENP3 in vascular remodeling, SENP3 +/− mice and wild-type (WT) littermates were subjected to partial ligation of left common carotid artery (LCCA).…”

High SENP3 Expression Promotes Cell Migration, Invasion, and Proliferation by Modulating DNA Methylation of E-Cadherin in Osteosarcoma

“…As a member of the SUMO-specific protease family, the function of SENP3 is known to regulate deSUMOylation of chromosome-associated proteins and chromosome stability in multiple cellular biological processes. 26 , 27 Hypoxia is a common phenomenon in human solid tumors. Recent studies have shown that SENP3 is a sensitive redox sensor, as SENP3 upregulation in cells is triggered by oxidative modification and is responsible for HIF-1α transactivation.…”