Posttranslational regulation of CREB-binding protein expression by F-box leucine-rich repeat-containing protein 19 and ubiquitin-specific peptidase 14 in the paraventricular nucleus participates in chronic stress-induced symptomatology via the modulation of the hypothalamic‒pituitary‒adrenal axis.

Abstract

The precise molecular mechanism by which chronic stress promotes the overexpression of corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) remains incompletely understood. Previous studies have revealed that cAMP-response element binding (CREB)-binding protein (CBP) directly participates in the regulation of CRH expression. The ubiquitination/degradation and deubiquitination/stabilization of CBP are regulated by F-box leucine-rich repeat-containing protein 19 (FBXL19) and ubiquitin-specific peptidase 14 (USP14), respectively. We hypothesized that the FBXL19-USP14-CBP system in the PVN might contribute to chronic stress-induced CRH release, and various methods were employed in this study. Our results revealed that both chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) induced significant changes in the FBXL19-USP14-CBP system in the PVN of mice. Genetic knockdown of FBXL19, genetic overexpression of USP14/CBP, and stereotactic infusion of TAT-USP14 in the PVN all simulated chronic stress, inducing a similar symptomatology in naïve mice, and this effect was mediated by increased CRH biosynthesis, which required both the CBP‒CREB interaction and the acetyltransferase activity of CBP. In contrast, genetic overexpression of FBXL19 and genetic knockdown of USP14/CBP in the PVN reversed chronic stress-induced symptomatology in mice. Similarly, stereotactic infusion of TAT-FBXL19 into the PVN and intraperitoneal injection of IU1 also reversed chronic stress-induced symptomatology in mice. In addition, genetic knockout of USP14 and FBXL19 prevented and aggravated chronic stress-induced symptomatology in mice, respectively. Collectively, FBXL19, USP14, and CBP in PVN neurons correlate with chronic stress, and they could be viable targets for treating chronic stress-related neuropsychiatric disorders such as depression.