Ubiquitin inhibitor

Ubiquitination refers to the process by which ubiquitin (a class of low molecular weight proteins) molecules classify proteins in cells under a series of special enzymes, select target protein molecules, and specifically modify target proteins. These special enzymes include ubiquitin activating enzymes, binding enzymes, ligases and degrading enzymes. Ubiquitination plays an important role in the localization, metabolism, function, regulation and degradation of proteins. At the same time, it is also involved in the regulation of cell cycle, proliferation, apoptosis, differentiation, metastasis, gene expression, transcriptional regulation, signal transmission, injury repair, inflammatory immunity and almost all life activities. Ubiquitination is closely related to the pathogenesis of diseases such as cancer and cardiovascular disease. Therefore, as a major achievement in biochemistry research in recent years, it has become a new target for research and development of new drugs. The process of protein ubiquitination also plays a key role in the regulation of the human immune system. Like the phosphorylation modification process, the ubiquitination modification process is also a reversible covalent modification process that regulates the stability, functional activity, and intracellular localization of the modified protein. Therefore, ubiquitination plays an important role in the development of the human immune system and in various stages of the immune response, such as the initiation, development and termination of immune responses. Recent studies have shown that several ubiquitin ligases are involved in the process of preventing the immune system from attacking autologous tissues. The dysfunction of these ubiquitin ligases is associated with autoimmune diseases. A safe and effective immune system should be able to effectively remove or limit the pathogens of various invading organisms without attacking their own tissues. To achieve this goal, the immune system must be very finely regulated. As a very important means of regulation in the body, the ubiquitination modification pathway has undoubtedly played an important role in the regulation of the immune system. Early research on this subject has focused on the NF-κB pathway. In recent years, studies have found that the ubiquitination pathway activates the NF-κB pathway through several signaling pathways, which play a regulatory role in the activation of NF-κB. The NF-κB pathway plays a key role in both innate and acquired immunity, so we are beginning to recognize the regulation of the ubiquitination pathway on the immune system. Ubiquitin is a very conserved polypeptide consisting of 76 amino acid residues that can catalyze a series of enzymatic reactions, such as E1, E2, and E3, with one or more lysine residues on intracellular target proteins. The base is covalently linked. The ubiquitin protein itself also contains seven lysine residues, so that they can also be linked to each other through these sites to form a polyubiquitin chain. Current studies have shown that if a polyubiquitin protein chain is linked to the 48th lysine residue on the modified protein, it will mediate the degradation of the target protein into the proteasome; if other sites on the modified protein, such as When the 63 lysine residues are linked, the target protein can function as a signaling pathway without being degraded. In addition, some proteins, such as histones H2A and H2B, can also be regulated without degradation by monoubiquitin. Like the phosphorylation pathway, the ubiquitination pathway is also reversible, ie the ubiquitin protein modification can be removed by deubiquitinating enzyme (DUB), a reversible modification pathway that is well suited for regulation of the immune system. mechanism. After the target protein is modified by the ubiquitination pathway, the ubiquitin protein monomer or multimer attached to the target protein can be recognized and bound by various ubiquitin protein binding domains (UBDs). The human proteome contains two E1 enzymes, 50 E2 enzymes, 600 E3 enzymes, 90 DUB enzymes and 20 UBDs, indicating how important the ubiquitin modification pathway plays in cell regulation. The E3 enzyme is a key enzyme in the ubiquitin-modifying pathway that determines substrate specificity. It can be divided into two broad categories, namely the E3 enzyme containing the HECT domain and other RING-containing domains or RING-like domains (such as U-box or P3 domain) E3 enzyme. Both E3 enzymes play a key role in the immune regulation process.