Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system
Introduction
The ubiquitin–proteasome system (UPS) is one of the major cellular pathways controlling protein turnover in eukaryotic cells. The UPS is a complex proteolytic pathway that degrades proteins. Ubiquitination is a process whereby target proteins can be marked for degradation by the proteasome. It is a multi-step enzymatic process, using three classes of enzymes (E1s, E2s, and E3s), and involves the sequential transfer of ubiquitin from these enzymes to a lysine residue on the target protein [1]. Ubiquitin, a 76 amino acid protein, is first activated by the ubiquitin-activating enzyme (E1) in an ATP-dependent reaction in which the C-terminal glycine residue of ubiquitin binds to the active-site cysteine of an E1 in a thioester linkage. The activated ubiquitin is passed to E2 ubiquitin-conjugation enzymes and then to E3 ubiquitin ligases, which target specific proteins for ubiquitination. The timing and location of ubiquitination is controlled by the E3 ligase. E3 ligases fall into two categories. The first is characterized by a zinc-binding RING (really interesting new gene) finger domain that promotes ubiquitination by binding a substrate and an E2. The second group, called HECT (homologous to E6-AP carboxy-terminus) domain ligases, forms a high-energy thiolester bond with ubiquitin and then transfers the activated ubiquitin directly to protein substrates. There are significant but limited numbers of ubiquitin-carrier enzymes (E2s), and a much larger number of ubiquitin ligases (E3s). Thus, the ubiquitination enzymes form a hierarchical cascade, with specificity of substrate recognition being attributable to the various combinations of E2 and E3 pairs.
Ubiquitination can be reversible. DUBs are cysteine proteases that generate free usable ubiquitin from several sources including ubiquitin–protein conjugates, ubiquitin-adducts and ubiquitin precursors. The 26S proteasome is formed by the co-assembly of a 20S proteasome catalytic core and 19S regulatory cap. The 20S proteasome is a self-compartmentalizing protein assembly with a barrel shape containing various proteolytic activities. The 19S subunits contain several ATPases that are involved in opening the pore of the 20S proteasome, unfolding the target proteins as they enter the proteasome and trans-locating the proteins into the interior of the proteasome. The targeting of substrates to the proteasome is accomplished through the recognition of polyubiquitin chains by the non-ATPase subunits of the 19S cap [2].
Ubiquitination has also emerged as a key regulatory mechanism of protein interaction and trafficking. Mono-ubiquitination of integral membrane proteins functions as a signal for their removal and downregulation from the plasma membrane [3]. In summary, the UPS provides a highly regulated mechanism to control protein stability, activity and localization in cells.
Many of the first insights of UPS function in neurons came from studies of neurodegenerative disease. This has been increasingly evident from the number of neurodegenerative diseases that are characterized by aggregates and inclusions of aberrantly ubiquitinated proteins, inferring a defect in UPS function. These studies highlighted basic questions that have now become central to recent work on UPS function in normal neuronal physiology. Most importantly, what are the synaptic targets and components of the UPS that facilitate the development and selective remodeling of synaptic connections in the nervous system? In addition, as the UPS provides a way to confer spatial and temporal regulation on a given pathway. Therefore, the obvious question of how synaptic activity recruits and is regulated by UPS function comes to the forefront. Here, I review the most recent work that attempts to extract observations that are central to these basic questions.
Section snippets
Brain development and cell migration
Just as important as synapse formation is the proper development and coordinated migration of different neuronal populations in the brain. Reelin, a large glycoprotein that is secreted by specific neurons, plays a crucial role in the migration of several populations of neurons in cortex of the mammalian central nervous system (CNS). Reelin binds to the very low density lipoprotein receptor (VLDLR) and the ApoE receptor 2 (ApoER2) on target neurons, thereby coordinating their proper migration in
Axon outgrowth and guidance
Extrinsic and intrinsic guidance cues help to navigate axons to their target destinations. At the helm is the axonal growth cone, the primary job of which is to rapidly decode guidance cues and convert them into directional decisions. Various signaling guidance molecules such as netrins, semaphorins, ephrins and Slits have been linked to pathways that control growth cone dynamics. One of the first demonstrations of UPS function in growth cones was provided by the Campbell and Holt [10]. In
Synapse development
Some of the best supported evidence for UPS function in synapse development has come from genetic studies in Drosophila and C. elegans. In Drosophila, Fat facets (faf) and Highwire (hiw), genes that code for a DUB and a ubiquitin ligase, respectively, control synaptic growth at the neuromuscular junction (NMJ) by directly antagonizing each others action [17, 18]. Highwire negatively regulates presynaptic bone morphogenic protein (BMP) signaling cascades through interactions with the Smad
Presynaptic and postsynaptic function
Neurotransmitter release depends on the highly orchestrated recycling dynamics of synaptic vesicles. Mono-ubiquitination regulates the precise timing for association of components of the endocytic machinery. A recent study by Chen et al. [26] provides good evidence that synaptic stimulation can induce rapid (within seconds) and reversible decreases in the ubiquitination state of proteins at axon terminals. This is probably facilitated by de-ubiquitinating enzyme activity that is dynamically
Conclusions
A major aspect of UPS function is the dynamic control of protein stability, and thus protein activity. It has become increasingly apparent that the concerted control of protein synthesis and protein degradation is crucial for synapse development and function. It is likely that many synaptic activities elicit both protein synthesis and degradational cues. The recent work reviewed here addresses, most notably, the identification of synaptic targets and synaptic components of the UPS. In addition,
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (38)
Gettin’ down with ubiquitin: turning off cell-surface receptors, transporters and channels
Trends Cell Biol
(1999)- et al.
Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2
Cell
(1999) - et al.
Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development
Curr Biol
(2003) - et al.
Reelin activates SRC family tyrosine kinases in neurons
Curr Biol
(2003) - et al.
Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled-1
J Biol Chem
(2004) - et al.
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
J Biol Chem
(2002) - et al.
Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation
Neuron
(2001) - et al.
Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones
Neuron
(2003) - et al.
Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor
Neuron
(2002) - et al.
Highwire regulates synaptic growth in Drosophila
Neuron
(2000)
Highwire regulates presynaptic BMP signaling essential for synaptic growth
Neuron
Rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans
Neuron
Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain
Neuron
Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development
Cell
Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis
Neuron
LIN-23-mediated degradation of beta-catenin regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of C. elegans
Neuron
AMPA receptor trafficking and synaptic plasticity
Annu Rev Neurosci
Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system
Nat Neurosci
Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression
Neuron
Cited by (91)
Dietary zinc inadequacy affects neurotrophic factors and proteostasis in the rat brain
2023, Nutrition ResearchTargeting immunoproteasome in neurodegeneration: A glance to the future
2023, Pharmacology and TherapeuticsDynamics and distribution of endosomes and lysosomes in dendrites
2022, Current Opinion in NeurobiologyAge-related neuronal damage by advanced glycation end products through altered proteostasis
2022, Chemico-Biological Interactions