A Putative Role for Ubiquitin-Proteasome Signaling in Estrogenic Memory Regulation

Abstract

Sex steroid hormones such as 17β-estradiol (E₂) are critical neuromodulators of hippocampal synaptic plasticity and hippocampus-dependent memory in both males and females. However, the mechanisms through which E₂ regulates memory formation in both sexes remain unclear. Research to date suggests that E₂ regulates hippocampus-dependent memory by activating numerous cell-signaling cascades to promote the synthesis of proteins that support structural changes at hippocampal synapses. However, this work has largely overlooked the equally important contributions of protein degradation mediated by the ubiquitin proteasome system (UPS) in remodeling the synapse. Despite being critically implicated in synaptic plasticity and successful formation of long-term memories, it remains unclear whether protein degradation mediated by the UPS is necessary for E₂ to exert its beneficial effects on hippocampal plasticity and memory formation. The present article provides an overview of the receptor and signaling mechanisms so far identified as critical for regulating hippocampal E₂ and UPS function in males and females, with a particular emphasis on the ways in which these mechanisms overlap to support structural integrity and protein composition of hippocampal synapses. We argue that the high degree of correspondence between E₂ and UPS activity warrants additional study to examine the contributions of ubiquitin-mediated protein degradation in regulating the effects of sex steroid hormones on cognition.

Keywords: 17β-estradiol; hippocampus; memory; proteasome; protein degradation; ubiquitin.

Figure 1

Schematic diagram illustrating a model of the mechanisms through which E₂ regulates CA1 spine density and memory. E₂ acts via membrane-associated receptors like mGluRs, GPER, and TrkB, as well as ion channels like NMDAR, to stimulate cell-signaling kinases that promote local protein synthesis and actin polymerization. ERα and ERβ promote protein synthesis via ERK and mTOR signaling, whereas GPER promotes actin polymerization through JNK signaling. Illustration created using BioRender.com.

Figure 2

Ubiquitin-mediated proteolysis. (A) Schematic illustration of ubiquitin targeting pathway. Free ubiquitin molecules are activated by E1-activating ligases via ATP hydrolysis. Activated ubiquitin is then bound to E1, which then transfers the active ubiquitin molecule to E2 carrier enzymes. E3 ligases bind to target substrates destined for degradation. E2 enzymes localize to the E3-substrate complex, enabling the transfer of active ubiquitin to substrate protein. Additional ubiquitin molecules attach at lysine-48 (K48) residues on subsequent ubiquitin, eventually forming a K48-linked polyubiquitin chain that is destined to the 26S proteasome for proteasomal degradation. (B) Detailed schematic view of the 26S proteasome. The 26S proteasome contains one or two 19S caps and a 20S core. K48-linked polyubiquitinated protein binds to the 19S regulatory cap at ubiquitin binding sites. Upon activation of the proteasome, which usually occurs at the 19S subunit Rpt6 (Ser¹²⁰ residue), the polyubiquitin chain becomes hydrolyzed and the substrate protein unfolds to allow β subunits in the 20S core to hydrolyze proteins via caspase-, trypsin-, and chymotrypsin-like activities. Illustration created using BioRender.com.

Figure 3

Hypothesized mechanisms through which E₂ may activate the UPS to regulate CA1 dendritic spine density and hippocampal memory. E₂ acts via membrane-associated estrogen receptors including ERα and ERβ to promote postsynaptic sensitivity to glutamate (red circle on NMDAR) and opening of NMDARs. E₂-induced NMDAR activation promotes an increase in the amount of substrate proteins that acquire a K48-polyubiquitin tag through the actions of E1-E3 ubiquitin ligases (left). NMDAR activation also simultaneously permits an influx of intracellular Ca²⁺ which results in an E₂-induced increase in CaMKII and PKA activity (right). CaMKII and PKA then phosphorylate the Rpt6 subunit of the 26S proteasome complex, which mobilizes proteasomes to dendritic spine shafts to initiate the breakdown of K48-tagged substrate proteins. Illustration created using BioRender.com.