Association Between Neddylation and Immune Response

Abstract

Neddylation is a ubiquitin-like post-translational protein modification. It occurs via the activation of the neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8) by three enzymes: activating enzyme, conjugating enzyme, and ligase. NEDD8 was first isolated from the mouse brain in 1992 and was initially considered important for the development and differentiation of the central nervous system. Previously, the downregulation of neddylation was associated with some human diseases, such as neurodegenerative disorders and cancers. In recent years, neddylation has also been proven to be pivotal in various processes of the human immune system, including the regulation of inflammation, bacterial infection, viral infection, and T cell function. Additionally, NEDD8 was found to act on proteins that can affect viral transcription, leading to impaired infectivity. Here, we focused on the influence of neddylation on the innate and adaptive immune responses.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3–TBK1–IRF3 complex

“…By screening the protein–protein interaction networks, we found that NEDD8 might serve as a potential target of FBXO11. NEDD8 is characterized as a type of posttranslational protein modification that binds to the target protein via a process similar to ubiquitination 44 . Both IRF3 and IRF7 served as potential substrates of neddylation during virus infection and can inspire antiviral responses 44 .…”

“…NEDD8 is characterized as a type of posttranslational protein modification that binds to the target protein via a process similar to ubiquitination 44 . Both IRF3 and IRF7 served as potential substrates of neddylation during virus infection and can inspire antiviral responses 44 . NEDD8 directly targets the C‐terminal lysine residues of IRF7 and enhances its transcription by promoting IFN‐I signaling after infection with the SeV virus 45 .…”

“…44 NEDD8 directly targets the C-terminal lysine residues of IRF7 and enhances its transcription by promoting IFN-I signaling after infection with the F I G U R E 6 F-box protein 11 (FBXO11) participated in the host antiviral response in vivo. (A-C) Quantitative real-time polymerase chain reaction (PCR) was used to analyze the messenger RNA (mRNA) expression of Fbxo11 in the liver (A), spleen (B), and lung (C) of C57BL/6 mice after vesicular stomatitis virus-GFP (VSV-eGFP) infection at time points of 0, 2, 6, 12, 24, and 48 h (n = 6).…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“… 1453 At present, the primary approach to studying the neddylation pathway involves interfering with the expression of particular genes through siRNA or inhibiting the activation enzyme NAE using small molecule inhibitors such as MLN4924 which deactivate the entire neddylation pathway. 1454 The formation of a stable covalent bond with NEDD8 and competitive inhibition of NAE's activation of NEDD8 leads to inhibition of the neddylation pathway and partially blocks the ubiquitination pathway dependent on CRL. This inhibition results in the accumulation of substrates, triggering various cellular responses, such as cell cycle arrest, apoptosis, aging, and autophagy.…”

“…Many recent studies have shown that NEDD8 or enzymes related to the neddylation pathway are overexpressed in various cancers, including lung cancer, 1451 liver cancer, 1452 CRC, 1449 and esophageal squamous cell carcinoma 1453 . At present, the primary approach to studying the neddylation pathway involves interfering with the expression of particular genes through siRNA or inhibiting the activation enzyme NAE using small molecule inhibitors such as MLN4924 which deactivate the entire neddylation pathway 1454 . The formation of a stable covalent bond with NEDD8 and competitive inhibition of NAE's activation of NEDD8 leads to inhibition of the neddylation pathway and partially blocks the ubiquitination pathway dependent on CRL.…”