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

Abstract

Summary 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 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. While 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.

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

“…This includes sensory neurons, the nerve ring (a central bundle of hundreds of axons), and the motor neurons of the nerve cord ( Fig. 1c) [18]. The broad expression of Huwe1 in adult mammalian and C. elegans nervous systems is consistent with Huwe1 having widespread, important roles in the nervous system, which we discuss further.…”

“…The RPM-1/FSN-1 ubiquitin ligase complex is an important regulator of axon termination in C. elegans [35,36], and functions as both a ubiquitin ligase and a signaling hub to affect numerous downstream signaling pathways [31,[37][38][39][40][41][42]. In two different eel-1 (lf) mutants, low levels of axon termination defects were observed in two types of neurons, the SAB motor neurons and the mechanosensory neurons that sense gentle touch [18]. Interestingly, eel-1; fsn-1 double mutants had strong enhancer effects indicating that EEL-1 and FSN-1 function in parallel pathways to regulate axon termination.…”

egl-4 modulates electroconvulsive seizure duration in C. elegans

“…Our laboratory has used Retigabine with C. elegans in the past to show that human seizure therapeutics can successfully be used to alter recovery time in invertebrates; however, regarding N2, the drug must be used in conjunction with a chemical convulsant to induce an effect (Opperman et al 2017; Risley et al 2016). We hypothesize this is due to the increased seizure threshold for N2.…”

Role of HECT ubiquitin protein ligases in Arabidopsis thaliana

“…Studies in animals have shown that they play a key role in protein degradation and DNA damage related. In recent years, studies have found that human HECT E3s is also closely linked to the occurrence of various diseases such as cancer [8,36,37].…”