Phosphorylation of PEA‐15 in HIV‐TAT Mediated Disruption of Blood‐Brain Barrier

Abstract

Trans‐activator of transcription, TAT, one of the proteins that is expressed by the HIV genome, has been heavily associated with HIV‐associated cognitive morbidities. In vitro experiments have shown that the presence of TAT disrupts blood‐brain barrier (BBB) tight junctions and overall integrity. The mechanisms for TAT associated BBB disruption remain largely unknown.Phosphoprotein enriched in astrocytes (PEA‐15) is a ubiquitously expressed protein that is best known for its ability to regulate critical cellular pathways via protein‐protein interactions. PEA‐15 gains multiple protein binding affinities depending on the phosphorylation states of its residues Ser104 and Ser116. When PEA‐15 is phosphorylated at both Ser104 and Ser116 it gains high affinity to the Fas‐associated death domain (FADD). When protein‐protein binding with FADD, PEA‐15 blocks FADD from inducing apoptosis by preventing it from activating Caspase‐8.By blocking FADD effector functions via transfecting a phosphomimetic mutant of PEA‐15, in which both Ser104 and Ser116 are replaced with Aspartic Acid (PEA‐15‐DD), into primary human brain microvascular endothelial cells, we set to explore the mechanisms of HIV‐TAT mediated disruption of BBB tight junctions.Support or Funding InformationThis research is supported by NIH Grant R21DA046223This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.