The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation

Abstract

Over the last 20 years, a number of studies have provided strong support for protein degradation mediated by the ubiquitin-proteasome system in synaptic plasticity and memory formation. In this system, target substrates become covalently modified by the small protein ubiquitin through a series of enzymatic reactions involving hundreds of different ligases. While some substrates will acquire only a single ubiquitin, most will be marked by multiple ubiquitin modifications, which link together at specific lysine sites or the N-terminal methionine on the previous ubiquitin to form a polyubiquitin chain. There are at least eight known linkage-specific polyubiquitin chains a target protein can acquire, many of which are independent of the proteasome, and these chains can be homogenous, mixed, or branched in nature, all of which result in different functional outcomes and fates for the target substrate. However, as the focus has remained on protein degradation, much remains unknown about the role of these diverse ubiquitin chains in the brain, particularly during activity-and learning-dependent synaptic plasticity. Here, we review the different types and functions of ubiquitin chains and summarize evidence suggesting a role for these diverse ubiquitin modifications in synaptic plasticity and memory formation. We conclude by discussing how technological limitations have limited our ability to identify and elucidate the role of different ubiquitin chains in the brain and speculate on the future directions and implications of understanding linkage-specific ubiquitin modifications in activity-and learning-dependent synaptic plasticity.

Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

“…This may explain why SHANK, MOV10 and IkB were not identified as significant targets of K48 in either sex during fear memory formation in our dataset, despite previous evidence demonstrating proteasome-mediated degradation of these proteins following learning (Lopez-Salon et al, 2001 ; Yeh et al, 2002 ; Lee et al, 2008 ; Jarome et al, 2011 ). Furthermore, this could have occurred due to these putative degradation targets being marked by a polyubiquitin chain carrying another linkage site, such as K11 (Xu et al, 2009 ; Meyer and Rape, 2014 ; Meza Gutierrez et al, 2018 ; Musaus et al, 2020 ). Unfortunately, until more precise technology is developed, the specific role of K48 polyubiquitination in fear memory formation in any brain region will remain equivocal.…”

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

“…Outside of protein degradation, the UPS performs a variety of other cellular functions, primarily through a number of different types of polyubiquitin chains (reviewed in, Musaus et al, 2020). For example, while lysine 11 (K11) and 48 (K48) polyubiquitin chains are primarily involved in protein degradation, lysine 63 (K63) polyubiquitin chains have been shown to be involved in a variety of cellular processes that include the DNA damage response, intracellular trafficking, and endocytosis (Nathan et al, 2013;Erpapazoglou et al, 2014;Lee et al, 2017).…”

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

“…After the first ubiquitin is bound to the substrate protein, another ubiquitin becomes attached to an internal lysine residue on the first ubiquitin, eventually forming a polyubiquitin chain. Substrate proteins can acquire several different types of ubiquitin “tags,” however, those that receive a lysine-48 (K48) polyubiquitin tag become targets for degradation by the 26S proteasome complex (Glickman and Ciechanover, 2002 ; Musaus et al, 2020 ).…”