The pivotal roles of neddylation pathway in immunoregulation

Abstract

Introduction Protein neddylation, one of the most important posttranslational modifications that tagging neuronal precursor cell‐expressed developmentally downregulated protein 8 onto substrate proteins, plays fundamental roles in the process of many cellular functions. A number of studies have demonstrated the critical roles of neddylation modification in multiple pathophysiological processes, but its regulatory role in the immune system has only been finitely unveiled. Methods In this review, the latest advances in the field of neddylation modification in regulating the immune responses are succinctly discussed. Results Neddylation modification acts as a crucial modulator of innate immune cells (neutrophils, macrophages, and dendritic cells) and lymphocytes. Dysregulation of neddylation alters characteristics and functions of those cells due to abnormal degradation of key signaling molecules involved in immunoregulation. Furthermore, the ectopic immune responses caused by the abnormal neddylation play pivotal roles in a variety of immune‐related diseases, such as infection, inflammation, and cancer. Conclusions The pivotal roles of neddylation pathway in immunoregulation are attracted more and more attention, which may provide new insights into the pathogenesis of a variety of immune‐related diseases and help to indicate new therapeutic targets and potential treatment strategies.

Neddylation Inhibition Causes Impaired Mouse Embryo Quality and Blastocyst Hatching Failure Through Elevated Oxidative Stress and Reduced IL-1β

“…As the main pathway of protein degradation, ubiquitination and its new forms have been well studied. Neddylation, a ubiquitination-like modification, has been shown to participate in a large variety of cellular processes and to be involved in modulating cell-cell and cell-microenvironment interactions ( 9 , 10 ), for example, immune-related conditions including inflammation and cancer ( 11 ). Previous works also showed that neddylation plays a significant role in mammalian oocyte maturation and early embryonic development ( 12 , 13 ).…”

Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients

“…In the last years, many researchers have described the relevant role of the post-translational modification (PTM) known as neddylation in the activation of the immune response and regulation of viral infections [ 7 ]. Neddylation is a reversible PTM characterized by the covalent conjugation of a small peptide NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to lysine of target proteins in order to modulate their stability, localization, activity and function [ 8 , 9 ].…”

“…The neddylation process is a highly conserved PTM that allows the cell to respond and adapt quickly and efficiently to various stimuli [ 10 ]. Under physiological conditions, neddylation levels are low, but overactivation of neddylation takes place as a response to cellular stress or DNA damage [ 11 , 12 ], such as during a viral infection, inflammation, or cancer [ 7 , 13 – 15 ], changing the proteome homeostasis and affecting the metabolism and functionality of the immune cells [ 7 , 16 ]. In fact, a pharmacological inhibitor, MLN4924, was developed which selectively acts on NEDD8 activating enzyme 1 (NAE1) by forming covalent adducts and inhibiting its activity [ 15 ].…”

Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

“…Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8), to selected substrate proteins, affecting their stability, conformation/function, and subcellular localization; this in turn can regulate many biological and pathological processes, including cancer progression and immune response [ 1 – 4 ].…”