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

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.

Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2

“…In reality, such drugs also need to be specific since cellular immune functions may also have housekeeping roles. One class of inhibitors is based on the fact that Cullins are activated by conjugation of the ubiquitin-like protein NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8), through a process known as NEDDylation [ 165 , 166 ]. Two small-molecule inhibitors of NEDDylation, viz.…”

SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone

“…NEDDylation of cullins is essential for the correct function of the CRL E3 ligases: deregulated NEDDylation leads to dysfunctional ubiquitination and eventually to dysregulation of cell cycle progression and cellular survival. The specific NEDDylation of cullins is referred as canonical NEDDylation and highlight the close connection between NEDDylation and ubiquitination ( Vijayasimha and Dolan, 2021 ; Ilic et al, 2022 ). However, a growing number of non-cullin targets have also been reported, as p53, Smurf1, PTEN, etc., ( Xirodimas et al, 2004 ; Xie et al, 2014 ; Xie et al, 2021a ), a process referred as non-canonical NEDDylation.…”

“…However, a growing number of non-cullin targets have also been reported, as p53, Smurf1, PTEN, etc., ( Xirodimas et al, 2004 ; Xie et al, 2014 ; Xie et al, 2021a ), a process referred as non-canonical NEDDylation. Non-canonical NEDDylation serves for the regulation of the activity and function of proteins: it has been reported to affect protein intracellular localization, protein stability both promoting degradation or protecting form it, and protein functions ( Vijayasimha and Dolan, 2021 ; Zou and Zhang, 2021 ). NEDDylation also regulates physiological and pathological processes such as immunity and inflammatory diseases, cellular response to stress, redox homeostasis, energy metabolism, and tumorigenesis ( Arenas et al, 2021 ; Zou and Zhang, 2021 ).…”

Targeting the deNEDDylating enzyme NEDP1 to ameliorate ALS phenotypes through Stress Granules dissolution

“…Based on the highly specific activity of NEDP1 to deconjugate NEDD8, understanding the biological role of this enzyme will also assist the elucidation of processes controlled by protein NEDDylation. Indeed, recent studies on NEDP1 identified roles for NEDD8 through modification of non-cullin substrates and the formation of poly-NEDD8 chains as cytoplasmic PQC signal in the DNA damage response (Bailly et al, 2019; Keuss et al, 2019; Meszka et al, 2022; Vijayasimha and Dolan, 2021).…”