Molecular Switches That Decide Brain Cell Survival: Phosphorylation Dependent Control of Inflammation and Cell Fate at the Blood–Brain Barrier
Yufeng Wei
College: Hennings College of Science Mathematics and Technology
Department: Chemistry & Physics
Abstract:
The blood–brain barrier is a critical protective interface that shields the brain from toxins, pathogens, and inflammatory damage. Disruption of this barrier is increasingly recognized as a contributing factor in neurological disorders associated with HIV infection, substance abuse, and chronic inflammation. This study investigates how cellular signaling events regulate the fate of human brain microvascular endothelial cells, a key cellular component of the blood–brain barrier.We focused on phosphorylation, a common molecular modification that acts as a regulatory “switch” controlling protein function. Using a combination of biochemical, structural, computational, and gene expression approaches, we examined how phosphorylation of the signaling protein PEA 15 alters its molecular interactions and downstream cellular outcomes following exposure to substances of abuse and the HIV 1 Tat protein. Structural modeling and molecular simulations revealed that phosphorylation induces distinct conformational changes in PEA 15, redirecting its binding partners and signaling pathways. To assess the cellular consequences of these changes, we analyzed gene expression profiles associated with programmed cell death and inflammation.Our findings reveal an unexpected molecular landscape in which HIV-1 and substances of abuse suppress the expression of key apoptotic and pyroptotic genes, while simultaneously enhancing pro-inflammatory cytokine signaling. This uncoupling of cell death pathways from inflammatory activation suggests a previously underappreciated mechanism by which endothelial cells may survive while promoting chronic inflammation at the blood–brain barrier.Together, these results identify phosphorylation-dependent signaling as a critical regulator of brain endothelial cell fate and inflammatory responses. This work provides new insight into how HIV infection and substance abuse may compromise brain health and highlights molecular signaling switches as potential therapeutic targets for preventing neurovascular dysfunction and neuroinflammation.