Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases

Abstract

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease associated with the central nervous system (CNS). Autoimmunity is caused by an abnormal immune response to self-antigens, which results in chronic inflammation and tissue death. Ubiquitination is a post-translational modification in which ubiquitin molecules are attached to proteins by ubiquitinating enzymes, and then the modified proteins are degraded by the proteasome system. In addition to regulating proteasomal degradation of proteins, ubiquitination also regulates other cellular functions that are independent of proteasomal degradation. It plays a vital role in intracellular protein turnover and immune signaling and responses. The ubiquitin–proteasome system (UPS) is primarily responsible for the nonlysosomal proteolysis of intracellular proteins. The 26S proteasome is a multicatalytic adenosine-triphosphate-dependent protease that recognizes ubiquitin covalently attached to particular proteins and targets them for degradation. Damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern many essential cellular functions, are removed by this degradation pathway. When this system is affected, cellular homeostasis is altered, resulting in the induction of a range of diseases. This review discusses the biochemistry and molecular biology of the UPS, including its role in the development of MS and proteinopathies. Potential therapies and targets involving the UPS are also addressed.

The emerging role of USP29 in cancer and other diseases

“…Abnormalities in the UPS are deeply involved in various human diseases, such as cancer, 4 Alzheimer's disease, 5 muscle atrophy, 6 and autoimmune diseases. 7 Additionally, the clinical efficacy of proteasome inhibitors, including bortezomib for multiple myeloma and other inhibitors, validates the therapeutic potential of this system. 8 Polyubiquitination of the target protein is fundamental to UPSmediated protein degradation; it is a reversible process and is catalyzed by deubiquitylating enzymes (DUBs).…”

“…The UPS comprises ubiquitin, ubiquitin‐activating enzyme E1, ubiquitin‐conjugating enzyme E2, ubiquitin ligase enzyme E3, and 26S proteasome 3 (Figure 1). Abnormalities in the UPS are deeply involved in various human diseases, such as cancer, 4 Alzheimer's disease, 5 muscle atrophy, 6 and autoimmune diseases 7 . Additionally, the clinical efficacy of proteasome inhibitors, including bortezomib for multiple myeloma and other inhibitors, validates the therapeutic potential of this system 8 …”

PROTACs: A novel strategy for cancer drug discovery and development

“…[19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years. 5,8,19,[42][43][44][45] At the present, more than 10 PROTAC degraders have entered clinical Phase I-II trials with ARV-471 and ARV-110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively.…”

“…TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

“… 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 …”