Journal Article

p62 Binding to Protein Kinase C Regulates HIV-1 gp120 V3 Loop Induced Microglial Inflammation

Wang, Linlin, Zuo, Qin, Dong, Jun, Rao, Yin, Gan, Limeng, Wang, Huili, Liu, Yuanyuan, Pan, Rui, Li, Xinyi

2025

Overview

The main pathogenic mechanism of HIV-associated neurocognitive disorders (HAND) is neuronal apoptosis induced by inflammatory mediators, in which microglial inflammation plays a crucial role. However, the exact pathogenic mechanism remains unclear. Previous studies have shown that the HIV-1 gp120 V3 loop can trigger inflammation in CHME-5 microglia. p62 is a post-translational modified multidomain protein that is involved in the regulation of autophagy and is closely related to neuroinflammation. In this study, we found that p62 knockout down-regulated the expression of MCP-1, IL-6 and COX-2, and improved the inflammation of HIV-1 gp120 V3 loop induced microglia, while overexpression of p62 up-regulated the expression of MCP-1, IL-6 and COX-2, and promoted the inflammation of microglia. In addition, protein kinase C (PKC) knockout down-regulated the expression of MCP-1, IL-6 and COX-2 and inhibited the activation of IKK/ NF-κ B pathway, while tumor necrosis factor receptor-associated factor 6 (TRAF6) knockout had no significant effect on the expression of MCP-1, IL-6 and COX-2. Co-immunoprecipitation showed that p62 was bound and interacted with PKC. Inhibition of IKK/ NF-κ B pathway can down-regulate the expression of MCP-1, IL-6 and COX-2, and improve the inflammatory response of microglia. Our research further found that inhibition of IKK/ NF-κ B can decrease the expression of Caspase-3 and reduce the apoptosis of neurons in the co-culture of CHME-5 microglia and primary mouse neurons. The results of this study suggest that HIV-1 gp120 V3 loop induced CHME-5 microglial inflammation may be activated by the direct binding of p62 and PKC through the IKK/ NF-κ B signaling pathway, and these findings provide an important reference for the prevention and treatment of HAND.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Antibodies / Apoptosis / Autophagy / Biomedical and Life Sciences / Biomedicine / Caspase-3 / Cognition / Cytokines / Enzymes / Flow cytometry / Glycoprotein gp120 / HIV / HIV Envelope Protein gp120 - metabolism / HIV-1 / Human immunodeficiency virus / Humans / Immunology / Immunoprecipitation / Inflammation / Inflammation - metabolism / Interleukin 6 / Internal Medicine / Kinases / Mice / Microglia / Microglia - metabolism / Microglia - pathology / Microscopy / Molecular weight / Monocyte chemoattractant protein 1 / Nervous system / Pathogenesis / Pathology / Peptides / Pharmacology/Toxicology / Plasmids / Post-translation / Protein Binding / Protein kinase C / Protein Kinase C - metabolism / Proteins / Rheumatology / Sequestosome-1 Protein - metabolism / Signal transduction / TRAF6 protein / Variance analysis