CXCL12-Mediated Regulation of ANP32A/Lanp, A Component of the Inhibitor of Histone Acetyl Transferase (INHAT) Complex, in Cortical Neurons

Abstract

The chemokine receptor CXCR4 and its endogenous ligand, CXCL12, are involved in development and homeostasis of the central nervous system and in the neuropathology of various neuroinflammatory/infectious disorders, including neuroAIDS. Our previous studies have shown that CXCR4 regulates cell cycle proteins that affect neuronal survival, such as the retinoblastoma protein, Rb. These studies also suggested that Rb-mediated gene repression might be involved in the neuronal protection against NMDA exitotoxicity conferred by stimulation of the CXCL12/CXCR4 axis. In order to further test this hypothesis, we focused on the potential interaction of Rb with another protein implicated in regulation of gene expression, leucine-rich acidic nuclear protein (Lanp), also known as ANP32A/pp32/PHAP1. Lanp is a critical member of the protein complex inhibitor of histone acetyl transferase (INHAT), which prevents histone tail's acetylation, thus leading to transcriptional repression. Our data show that, in primary rat cortical neurons cultured for up to 30 days, Lanp is predominantly localized into the nucleus throughout the culture period, in line with in vivo evidence. Moreover, co-immunoprecipitation experiments show that endogenous Lanp interacts with Rb in neurons. Stimulation of CXCR4 by its endogenous ligand, CXCL12, increased Lanp protein levels in these neurons. Importantly, the effect of CXCL12 was preserved after exposure of neurons to NMDA. Finally, overexpression of exogenous Lanp in the neurons protects them from excitotoxicity. Overall, these findings suggest that Lanp can interact with Rb in both young and mature neurons and is implicated in the regulation of neuronal survival by CXCL12/CXCR4.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-010-9228-5) contains supplementary material, which is available to authorized users.