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Review
. 2021 Oct 5;10(10):2660.
doi: 10.3390/cells10102660.

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

Kartikeya Vijayasimha  1 , Brian P Dolan  1
Affiliations
Review

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

Kartikeya Vijayasimha et al. Cells. .

Abstract

Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) is a ubiquitin-like protein (UBL) whose canonical function involves binding to, and thus, activating Cullin-Ring finger Ligases (CRLs), one of the largest family of ubiquitin ligases in the eukaryotic cell. However, in recent years, several non-canonical protein substrates of NEDD8 have been identified. Here we attempt to review the recent literature regarding non-canonical NEDDylation of substrates with a particular focus on how the covalent modification of NEDD8 alters the protein substrate. Like much in the study of ubiquitin and UBLs, there are no clear and all-encompassing explanations to satisfy the textbooks. In some instances, NEDD8 modification appears to alter the substrates localization, particularly during times of stress. NEDDylation may also have conflicting impacts upon a protein's stability: some reports indicate NEDDylation may protect against degradation whereas others show NEDDylation can promote degradation. We also examine how many of the in vitro studies measuring non-canonical NEDDylation were conducted and compare those conditions to those which may occur in vivo, such as cancer progression. It is likely that the conditions used to study non-canonical NEDDylation are similar to some types of cancers, such as glioblastoma, colon and rectal cancers, and lung adenocarcinomas. Although the full outcomes of non-canonical NEDDylation remain unknown, our review of the literature suggests that researchers keep an open mind to the situations where this modification occurs and determine the functional impacts of NEDD8-modification to the specific substrates which they study.

Keywords: NEDD8; post-translational modifications; ubiquitin-like proteins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Canonical and non-canonical NEDD8 substrates. Canonical NEDDylation refers to the post-translational modification of the Cullin family of proteins with NEDD8. NEDD8 is first activated by binding to the E1 NEDD8 activating enzyme, a process which can be blocked by the small molecule MLN4924. NEDD8 is then transferred via E2 and E3 enzymes to the Cullin protein, which in turn activates the CRL allowing it to transfer ubiquitin molecules to its designated substrate, leading to the substrate degradation. Non-canonical NEDDylation occurs when NEDD8 is covalently attached to protein substrates other than Cullin molecules. Following NEDDylation these proteins can adopt different fates, such as increased stability, increased enzymatic activity, changes in subcellular location, and degradation. Examples of substrates subject to these outcomes are listed. The list presented here is by no means exhaustive.
Figure 2
Figure 2
The TCGA Pan-Cancer was used to analyze 11,072 tumor samples for expression levels of UBA1, NEDD8, and UBC. Samples were ranked based upon UBA1 expression and visualized using Xena. (A) Visualization of total samples analyzed. (B) Visualization of 63 samples with the lowest level of UBA1 expression.
See this image and copyright information in PMC

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