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The mysterious role of NEDD8: How does it affect cell cycle and cytoskeletal regulation?
The biological function of NEDD8 protein in the human body is gradually gaining attention. NEDD8 is a ubiquitin-like (UBL) protein encoded by the NEDD8 gene, which is closely related to cell cycle progression and cytoskeletal regulation. Although it may seem like a minor role at first glance, NEDD8 plays an important role in cells that cannot be underestimated.
The amino acid sequence of human NEDD8 is 60% similar to that of ubiquitin, and the process of its covalent binding to specific proteins in cells is called NEDDylation, which is similar to the ubiquitination process.
The activation and binding process of NEDD8 is quite challenging. First, the C-terminal tail of NEDD8 needs to be processed before it can bind to cellular proteins. This process requires the assistance of NEDD8 to activate the E1 enzyme, which consists of two subunits. During this process, NEDD8 is activated and transferred to a specific E2 enzyme, which then interacts with a specific substrate through an E3 enzyme.
After activation, NEDD8 substrates are most prominently cullins, which are key components of the Cullin-RING ubiquitin ligase.
According to some of the latest studies, the removal of NEDD8 is equally important, and there are a variety of proteases that can accomplish this task, such as UCHL1, UCHL3, and some proteases that specifically target NEDD8, such as the COP9 signalosome and NEDP1. The actions of these proteases are crucial for cellular homeostasis.
The role of NEDD8 in DNA repair
NEDD8's role in DNA repair also cannot be ignored. The accumulation of NEDD8 at sites of DNA damage is a highly dynamic process. In particular, activation of NEDD8 is necessary to promote the DNA repair process after DNA damage caused by UV irradiation. Specifically, modification of NEDD8 helps increase the efficiency of the DNA repair pathway, effectively reducing DNA sensitivity.
In the NEDD8-regulated DNA repair process, the non-homologous end joining (NHEJ) pathway is used to repair double-strand breaks, and the first step of this process depends on the stability of the Ku70/Ku80 heterodimer.
NEDD8 in cancer chemotherapy
Studies have shown that NEDD8 may also play a key role in the progression of cancer cells. Certain DNA repair genes may become hypermethylated in a manner that promotes cancer. When NEDD8 activation is inhibited, this reduces the cell's ability to repair DNA, putting cancer cells at a greater risk of death.
In clinical trials from 2015 to 2016, the drug MLN4924 (Pevonedistat) demonstrated significant anti-tumor effects in the process of inhibiting NEDD8 activation.
Application in preclinical research
The study found that PPARγ, as a key factor in adipogenesis and lipid accumulation, is regulated by NEDD8 in its stability, and inhibiting NEDD8 can significantly reduce obesity caused by a high-fat diet. In addition, the study also found that NEDD8 can interfere with the transmission of NF-κB, further affecting its activity in leukemia cells.
As these studies progressed, the multiple roles of NEDD8 became clearer. From cell cycle regulation to DNA repair to cancer treatment, NEDD8 seems to be an invisible guardian in the cell. How will future research reveal more mysterious aspects of this little protein?
