Altered Proteasome Dynamics Promote Microglia-Mediated Neuroinflammation
Abstract
The ubiquitin proteasome system mediates multiple responses to cell stress and injury via controlled degradation of proteins by the constitutive proteasome. The system displays considerable plasticity that allows it to adapt to multiple cellular challenges. Trauma, stress and infection result in the assembly of the immunoproteasome, an inducible proteasome that has altered catalytic and protein processing properties compared to the constitutive proteasome. Previous studies provide evidence that the immunoproteasome is rapidly assembled in microglia following injury and selective immunoproteasome inhibition decreases cortical damage and attenuates inflammation. How the immunoproteasome components are assembled is a fundamental question towards understanding the process of protein degradation and inflammation in the central nervous system. We examined the mechanisms of immunoproteasome assembly in microglia by knocking down chaperone proteins that are known to be important for different stages of the assembly process. In addition, the role of the immunoproteasome on key microglia functions such as complement activation, cytokine release, phagocytosis and priming were explored in wild-type and immunoproteasome knock-out microglia. Our data suggest that in microglia, the immunoproteasome is formed from conversion of the existing constitutive proteasomes. Further, the immunoproteasome is involved in regulating multiple aspects of the microglial inflammation response by controlling activation of NF-kB via IkBa degradation. Taken together, these data highlight the possibility of targeting the immunoproteasome to control microglia-mediated neuroinflammation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 16, 2018
- Accession Number
- AD1128545
Entities
People
- Kasey E. Moritz
Organizations
- Uniformed Services University of the Health Sciences