Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease

Abstract

Huwe1 is a highly conserved member of the HECT E3 ubiquitin ligase family. Here, we explore the growing importance of Huwe1 in nervous system development, function and disease. We discuss extensive progress made in deciphering how Huwe1 regulates neural progenitor proliferation and differentiation, cell migration, and axon development. We highlight recent evidence indicating that Huwe1 regulates inhibitory neurotransmission. In covering these topics, we focus on findings made using both vertebrate and invertebrate in vivo model systems. Finally, we discuss extensive human genetic studies that strongly implicate HUWE1 in intellectual disability, and heighten the importance of continuing to unravel how Huwe1 affects the nervous system.

Keywords: Axon; EEL-1; HECT; Huwe1; Intellectual disability; Neural progenitor; Neuron; Neurotransmission; Transcription factor; Ubiquitin ligase.

Fig. 1

HUWE1 is evolutionarily conserved and broadly expressed in animal nervous systems. a Domain architecture of Huwe1 orthologs from Homo sapiens (Hs), Mus musculus (Mm), Danio rerio (Dr), Drosophila melanogaster (Dm) and Caenorhabditis elegans (Ce). b In situ hybridization of Huwe1 in mouse brain. Note Huwe1 is expressed throughout the brain with high expression in olfactory bulb (OB), cerebral cortex (CTX), hippocampus (HP) and cerebellum (CB). ceel-1 promoter driving GFP expression in C. elegans. eel-1 is widely expressed in the nerve ring and head neurons (left), and ventral nerve cord (right; bars = nerve cord; arrows = motor neuron cell bodies). Schematic denotes locations of images shown and axon bundles of the nerve ring and ventral nerve cord. DUF = conserved Domain of Unknown Function, UBA = Ubiquitin Associated domain, WWE = domain with conserved tryptophan (W) and glutamate (E) residues, UBM = Ubiquitin-Binding Motif (previously known as DUF4414), HECT = Homologous to the E6-AP Carboxyl Terminus (HECT)-type E3 ubiquitin ligase domain. For B, image credit: Allen Institute© 2007 Allen Institute for Brain Science. Allen Mouse Brain Atlas. Available from: https://mouse.brain-map.org/experiment/show/70445293. For C, images reprinted from Cell Reports, Vol. 19, Opperman, Mulcahy, Giles, Risley, Birnbaum, Tulgren, Dawson-Scully, Zhen, Grill, The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development, 822–835, Copyright 2017, with permission from Elsevier

Fig. 2

HUWE1 regulates neural development. (a and b) Shown to the left are diagrams of sagittal section of mouse brain. Boxes indicate a portion of (a) cerebral cortex and (b) cerebellar cortex. Center is a schematic of Huwe1 expression in neural progenitors that are proliferating, differentiating and migrating during development in (a) cerebral cortex and (b) cerebellar cortex (white = low expression, black = high expression). To the right are molecular pathways Huwe1 regulates to affect progenitor development in (a) cerebral cortex and (b) cerebellar cortex. Note that in the cerebellum Huwe1 potentially affects two pathways in different GNP populations. c Shown is a schematic of Q neuroblast migration in C. elegans which is mediated by Wnt signaling. To the left is the molecular mechanism by which EEL-1 and HUWE1 influence Wnt signaling in neuroblast migration and mammalian cell-based assays

Fig. 3

Huwe1 regulates inhibitory neurotransmission. a Schematic of a C. elegans motor circuit showing that EEL-1/HUWE1 is expressed in excitatory cholinergic and inhibitory GABAergic motor neurons, but preferentially affects GABAergic transmission. EEL-1 forms a complex with OGT-1 and functions parallel to OGT-1 to regulate GABA neuron function. b Schematic of excitatory and inhibitory connections to a mouse dorsal horn neuron in the spinal cord. Normally (left), glycinergic transmission inhibits excitatory input to nociceptive neurons. After peripheral tissue damage (right), Huwe1 is required to reduce glycinergic inhibitory transmission that stimulates inflammatory pain. This requires NMDAR-dependent recruitment of Huwe1, which ubiquitinates GlyRα1 and triggers GlyRα1 endocytosis (right). For A, diagram originally published in the Journal of Biological Chemistry. Giles, Desbois, Opperman, Tavora, Maroni, Grill. J. Biol. Chem. 2019; 294: 6843–6856.© Giles, Desbois, Opperman, Tavora, Maroni, Grill

Fig. 4

Mutations in HUWE1 associated with non-syndromic and syndromic forms of X-linked Intellectual Disability. Schematic of human HUWE1 and amino acid changes resulting from ID-associated mutations in HUWE1. ID-associated mutations occur broadly across the HUWE1 protein sequence with two hotspots, the HECT domain and DUF908 domain. Blue italics highlight two ID-associated mutations that were shown to result in loss-of-function when tested using in vivo assays of neuron function in C. elegans. Note three Conserved Domains (CD) of unknown function are annotated