The Protease Omi Cleaves the Mitogen-Activated Protein Kinase Kinase MEK1 to Inhibit Microglial Activation

Abstract

Inflammation in Parkinson's disease is closely associated with disease pathogenesis. Mutations in Omi, which encodes the protease Omi, are linked to neurodegeneration and Parkinson's disease in humans and in mouse models. The severe neurodegeneration and neuroinflammation that occur in mnd2 (motor neuron degeneration 2) mice result from loss of the protease activity of Omi by the point mutation S276C; however, the substrates of Omi that induce neurodegeneration are unknown. We showed that Omi was required for the production of inflammatory molecules by microglia, which are the resident macrophages in the central nervous system. Omi suppressed the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 and 2 (ERK1/2) by cleaving the upstream kinase MEK1 (mitogen-activated or extracellular signal-regulated protein kinase kinase 1). Knockdown of Omi in microglial cell lines led to activation of ERK1/2 and resulted in degradation of IκBα [α inhibitor of nuclear factor κB (NF-κB)], resulting in NF-κB activation and the expression of genes encoding inflammatory molecules, such as tumor necrosis factor-α and inducible nitric oxide synthase. The production of inflammatory molecules induced by the knockdown of Omi was blocked by the MEK1-specific inhibitor U0126. Furthermore, expression of the protease-deficient S276C Omi mutant in a microglial cell line had no effect on MEK1 cleavage or ERK1/2 activation. In the brains of mnd2 mice, we observed increased transcription of several genes encoding inflammatory molecules, as well as activation of astrocytes and microglia. Therefore, our study demonstrates that Omi is an intrinsic cellular factor that inhibits neuroinflammation.

Resveratrol attenuates HMGB1 signaling and inflammation in house dust mite-induced atopic dermatitis in mice

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ESE1 is Associated with Neuronal Apoptosis in Lipopolysaccharide Induced Neuroinflammation

“…Previous studies show that ESE1 regulates apoptosis of intestinal epithelial cells and promotes NF-κB activation [20,21]. Simultaneously, excessive inflammatory response leads to the secondary brain injury, including neuronal apoptosis [31].…”

“…Poly (AD P-ribose) polymerase-1 (PARP1) can be cleaved by apoptotic proteases, like caspase-3 and caspase-7 [15][16][17] and also plays a role in neuronal apoptosis so that we can take PARP1 as another maker of neuronal apoptosis. The activation of microglia and astrocytes causes neuronal apoptosis through the release of tumor necrosis factor α (TNF-α) and other pro-apoptosis cytokines [18][19][20]. Though lots of studies have revealed the biological process of neuroinflammation, the regulatory mechanisms of neuronal apoptosis under inflammation condition are not fully understood.…”

Protease Omi cleaving Hax-1 protein contributes to OGD/R-induced mitochondrial damage in neuroblastoma N2a cells and cerebral injury in MCAO mice

“…The oligonucleotide target sequences to Omi (si-Omi) or the negative control siRNA (si-NC) have been previously described [17,25] . The oligonucleotides were transfected with RNAiMAX (Invitrogen) following the manufacturer's instructions.…”

“…Mutations that cause loss of Omi protease activity are usually associated with neurodegeneration such as Parkinson's disease [16] . Omi is a protease that is able to cleave its substrates involved in both normal function and disease [17] . Upon apoptotic stimuli, Omi is released from the mitochondria into the cytosol and cleaves its substrates, such as inhibitor of apoptosis proteins (IAPs), thereby inducing apoptosis [18] .…”