Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Mar 31;23(7):3882.
doi: 10.3390/ijms23073882.

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

Shanez Haouari  1 , Patrick Vourc'h  1   2 , Médéric Jeanne  1   3 , Sylviane Marouillat  1 , Charlotte Veyrat-Durebex  1   2 , Débora Lanznaster  1 , Frédéric Laumonnier  1 , Philippe Corcia  1   4 , Hélène Blasco  1   2 , Christian R Andres  1   2
Affiliations
Review

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

Shanez Haouari et al. Int J Mol Sci. .

Abstract

The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.

Keywords: ALS; development; intellectual disability; ligases; neurodegenerative; ubiquitin.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of ubiquitination process by E3 ligases containing HECT domain. Ubiquitin is activated by an enzyme E1 and then transferred to E2 enzymes, and to a HECT E3 enzyme. The E3 enzyme transfers ubiquitin to the target protein, leading to its monoubiquitination or polyubiquitination. The E3 ligase contains 3 domains, an N-terminal C2 domain, a WW rich domain and a C-terminal domain organized into two lobes (N-lobe and C-lobe).
Figure 2
Figure 2
Structure of the 9 HECT E3 ligases of the NEDD4 subfamily. Protein size and domain conservation expressed as percentage of conservation compared to NEDD4.1 protein. Sequence of the nine members (UniprotKB) and identity percentage are obtained by alignment (MUSCLE) for the C2 and the HECT domains. Blue boxes represent the WW domains of each protein. Due to differences in the number of WW domains across proteins, identity percentage is not calculated for these domains.
Figure 3
Figure 3
Schematic representation of the roles played by E3 ligases of the HECT subfamily in cellular processes involved in CNS development and neurodegeneration. Substrates of these enzymes are presented in the references.
See this image and copyright information in PMC

References

    1. Gilbert S.L., Dobyns W.B., Lahn B.T. Genetic links between brain development and brain evolution. Nat. Rev. Genet. 2005;6:581–590. doi: 10.1038/nrg1634. - DOI - PubMed
    1. Upadhyay A., Joshi V., Amanullah A., Mishra R., Arora N., Prasad A., Mishra A. E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration. Front. Mol. Neurosci. 2017;10:151. doi: 10.3389/fnmol.2017.00151. - DOI - PMC - PubMed
    1. Hipp M.S., Kasturi P., Hartl F.U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 2019;20:421–435. doi: 10.1038/s41580-019-0101-y. - DOI - PubMed
    1. Ramocki M.B., Zoghbi H.Y. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature. 2008;455:912–918. doi: 10.1038/nature07457. - DOI - PMC - PubMed
    1. Wang C., Dong K., Wang Y., Peng G., Song X., Yu Y., Shen P., Cui X. Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma. BMC Cancer. 2021;21:890. doi: 10.1186/s12885-021-08631-9. - DOI - PMC - PubMed

MeSH terms

Substances