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

Huili Wang1, Qin Zuo1, Xinyi Li1

  • 1Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China.

Inflammation
|December 28, 2024
PubMed

Insights

This study reveals p62 and protein kinase C (PKC) interaction in HIV-1 gp120 V3 loop-induced microglial inflammation, offering new therapeutic targets for HIV-associated neurocognitive disorders (HAND).

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • HIV-associated neurocognitive disorders (HAND) involve microglial inflammation, but the precise mechanisms are unclear.
  • The HIV-1 gp120 V3 loop triggers microglial inflammation, and p62 is implicated in neuroinflammation regulation.
  • Understanding these pathways is crucial for developing effective HAND treatments.

Purpose of the Study:

  • To elucidate the role of p62 and its interaction with protein kinase C (PKC) in HIV-1 gp120 V3 loop-induced microglial inflammation.
  • To investigate the involvement of the IKK/NF-κB signaling pathway in this inflammatory process.
  • To identify potential therapeutic targets for mitigating HAND-related neuroinflammation and neuronal apoptosis.

Main Methods:

  • Utilized p62 knockout and overexpression in CHME-5 microglia to assess inflammatory marker expression (MCP-1, IL-6, COX-2).
  • Investigated the role of PKC and TRAF6 by knockout experiments and analyzed the IKK/NF-κB pathway activation.
  • Employed co-immunoprecipitation to confirm the interaction between p62 and PKC. Assessed neuronal apoptosis in co-culture models.

Main Results:

  • p62 knockout reduced inflammatory markers and microglial activation, while overexpression exacerbated them.
  • PKC knockout inhibited inflammatory markers and IKK/NF-κB pathway activation; TRAF6 knockout had no significant effect.
  • p62 directly binds and interacts with PKC, mediating inflammation via the IKK/NF-κB pathway.
  • Inhibition of IKK/NF-κB reduced inflammatory markers, decreased Caspase-3 expression, and attenuated neuronal apoptosis.

Conclusions:

  • HIV-1 gp120 V3 loop-induced microglial inflammation is mediated by the p62-PKC interaction, activating the IKK/NF-κB signaling pathway.
  • This pathway contributes to neuronal apoptosis, highlighting its significance in HAND pathogenesis.
  • Targeting the p62-PKC interaction or the IKK/NF-κB pathway presents a promising strategy for HAND prevention and treatment.
Keywords:
HIV-associated neurocognitive disordersIKK/ NF-κ B pathwayNeuroinflammationP62PKC

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