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What is NEDDylation? How does this process change the fate of proteins?
Inside cells, proteins play multiple roles, and the fulfillment of these roles is often regulated by various modifications. NEDDylation is an important protein modification process that, like another better-known modification process, ubiquitination, affects the life cycle and functional operation of cells. NEDD8 is a ubiquitin-like protein encoded by the NEDD8 gene in humans, and its corresponding name in mice and yeast is Rub1. The function of NEDD8 is closely related to its modification process, which not only affects the fate of the protein, but is also closely related to biological phenomena such as cell cycle, DNA repair and cancer.
After NEDD8 changes to a covalently bound form, it can affect the activity of specific proteins, and its regulatory ability changes the fate of these proteins to a certain extent.
Initiation and transmission of NEDDylation process
The process of NEDDylation is similar to ubiquitination and begins with the activation of NEDD8. NEDD8 requires specific enzymes for activation, a process accomplished by the NEDD8-activating E1 enzyme composed of APPBP1 and UBA3. During this process, UBA3 activates NEDD8 through an ATP-dependent reaction to form a high-energy thioester intermediate. After NEDD8 is activated, it is transferred to the UbcH12 E2 enzyme and finally binds to the specific substrate in the presence of the appropriate E3 enzyme.
Substrate and function of NEDD8
According to Brown et al., the most well-known substrates of NEDD8 are cullin proteins (such as CUL1 and CUL2), which are responsible for serving as molecular scaffolds for cullin-RING ubiquitin ligases (CRLs). NEDDylation covalently binds NEDD8 to a conserved lysine residue in cullin, which promotes the ubiquitination activity of CRL, resulting in semantic structural changes and optimizing ubiquitin transport to the target Transfer of protein.
NEDD8 removal mechanism
NEDD8 removal is primarily driven by several different proteases, such as UCHL1, UCHL3, and USP21, which have dual specificity for NEDD8 and ubiquitin. In addition, specific NEDD8 removal enzymes include the COP9 signaling complex, which can remove NEDD8 from cullin, as well as enzymes such as NEDP1 (also known as DEN1, SENP8).
The role of NEDD8 in DNA repair
When DNA is damaged, the accumulation of NEDD8 changes dynamically at the site of damage. The NEDDylation process in DNA stacking repair is a subpathway of global genome repair (GGR). In this process, the activation of Cul4A is essential for GGR-NER after DNA damage caused by UV radiation. In addition, NEDD8 also plays an important role in the repair of double-strand breaks, especially in the non-homologous end joining (NHEJ) pathway for repairing double-strand breaks.
Potential applications in cancer chemotherapyIn the NHEJ process, the formation of Ku70/Ku80 heteromers is the key first step, but these heteromers must be removed after repair, otherwise they will hinder transcription and replication.
The study suggests that excessive methylation of DNA damage repair genes may be an early step in cancer progression. Activation of NEDD8 plays an important role in DNA repair pathways such as NER and NHEJ. If NEDD8 activation is inhibited, insufficient DNA repair will lead to cell death, which may have a more significant impact on cancer cells than on normal cells. Related studies have shown that the anti-tumor drug Pevonedistat (MLN4924) can significantly improve the efficacy of cancer treatment and has shown optimistic results in multiple clinical trials.
Progress in preclinical research
NEDD8 activation and its interaction with PPARγ play a crucial role in adipogenesis and lipid accumulation. Pevonedistat has been shown to prevent high-fat diet-induced obesity and glucose intolerance in mice. In addition, NEDD8 has been found to inhibit the transport of NF-κB, and clinical studies using the same drug to target different cancer types are also actively underway.
NEDD8 and its modification pathways show diverse application possibilities, both in the regulation of cell functions and in the potential for cancer therapy. Could future research reveal more about this process and lead to new treatments?
