The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

Publication date: 25 April 2017
Source:Cell Reports, Volume 19, Issue 4
Author(s): Karla J. Opperman, Ben Mulcahy, Andrew C. Giles, Monica G. Risley, Rayna L. Birnbaum, Erik D. Tulgren, Ken Dawson-Scully, Mei Zhen, Brock Grill
Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology, and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission. Decreasing or increasing EEL-1 function alters GABAergic transmission and the excitatory/inhibitory (E/I) balance in the worm motor circuit, which leads to impaired locomotion and increased sensitivity to electroshock. Furthermore, multiple mutations associated with intellectual disability impair EEL-1 function. Although synaptic transmission defects did not result from abnormal synapse formation, sensitizing genetic backgrounds revealed that EEL-1 functions in the same pathway as the RING family ubiquitin ligase RPM-1 to regulate synapse formation and axon termination. These findings from a simple model circuit provide insight into the molecular mechanisms required to obtain E/I balance and could have implications for the link between HUWE1 and intellectual disability.

Graphical abstract

Teaser

Genetic changes in the HECT ubiquitin ligase EEL-1/HUWE1 are associated with intellectual disability. Using C. elegans, Opperman et al. show that EEL-1/HUWE1 is required for GABAergic presynaptic transmission and excitatory/inhibitory (E/I) transmission balance. These findings have potentially important implications for the link between HUWE1 and intellectual disability.


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