Deubiquitylating enzymes in neuronal health and disease

Abstract

Ubiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease.

Fig. 1. The ubiquitin system: ubiquitylation, ubiquitin recognition, and deubiquitylation.

a A schematic representation of ubiquitylation/deubiquitylation events of target proteins and the cellular outcome. b The ubiquitylation cascade by three types of enzyme: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). c The seven lysine residues and the N-terminal methionine (M1) are projected on the structure of ubiquitin (PDB code 1UBQ). d Principles of substrate recognition and ubiquitin cleavage by DUBs. e. Families of DUBs classified by sequence homology of their catalytic domains.

Fig. 2. An emerging model for DUB regulation of synaptic plasticity.

Activation of postsynaptic glutamate receptors controls neuron excitability. The postsynaptic density is enriched with a growing number of DUBs that antagonize E3-ligases and remove ubiquitin (Ub) chains, thereby protecting designated substrates from degradation by the lysosomes or the proteasome. Certain DUBs regulate the degradation and surface localization of the glutamate receptor, AMPAR. Moreover, a number of DUBs support the formation and function of the glutamatergic synapse by regulating the levels of scaffold proteins (SHANK and Ankyrin) and the leptin receptor (LepR). DUBs with yet unknown substrates are labeled with a question mark (?). The Ub symbol in this image indicates a polyubiquitin chain.

Fig. 3. Structure of USP46 and its regulatory partners.

a The structure of USP46 subdomains. Residues of the catalytic triad located at the interface between the palm and the thumb subdomains are shown as green sticks (PDB code 5L8H). b A model of USP46 complex based on superposition of the structures of USP46 with covalent ubiquitin (Ub-VME) (PDB code 5L8H) with the non-covalent complex of USP46:WDR20:WDR48 (PDB code 6JLQ).

Fig. 4. DUB involvement in neuron survival under normal conditions and in response to stressors.

The cell survival tyrosine receptor kinase B (TrkB) is activated by BDNF and is ubiquitylated by E3-ligases for degradation. The DUB, UCH-L1, deubiqutylates TrkB and thereby regulates TrkB levels and surface localization. The accumulation of aggregate-prone proteins (for example, α-synuclein) and damaged mitochondria are associated with neuronal loss in neurodegenerative diseases, such as Parkinson’s disease. These proteins and damaged mitochondria are ubiquitylated by E3-ligases (for example, parkin ubiquitylation of damaged mitochondria) and are engulfed by autophagosomes for degradation in the lysosome. A number of DUBs antagonize autophagy-mediated degradation of damaged mitochondria (USP30 and USP15) and α-synuclein (USP8). Moreover, other DUBs (ataxin-3, USP14 and USP12) are involved in promoting neuronal autophagy. DUBs with yet unknown substrates are labeled with a question mark (?). The Ub symbol in this image indicates a polyubiquitin chain.

Fig. 5. Structures of wild type and Parkinson’s disease-associated variants of UCH-L1.

a Superposition of the structures of wild-type apo and covalent bound ubiquitin to UCH-L1 is shown (PDB code 3KW5). Active site rearrangement and activation is due to ubiquitin binding. b Structures of the Parkinson’s disease variants, S18Y and I93M, are shown (PDB codes 3IFW and 3KVF) in comparison to the structure of wild-type UCH-L1 in complex with covalent ubiquitin.