Abstract
Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the regulation of tumor microenvironment through ubiquitination. Ubiquitination is a reversible protein post-translational modification that regulates various key biological processes, whereby ubiquitin is attached to substrates through a catalytic cascade coordinated by multiple enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. In contrast, ubiquitin can be removed by deubiquitinases in the process of deubiquitination. Here, we discuss the roles of E3 ligases and deubiquitinases as modulators of both cellular and non-cellular components in tumor microenvironment, providing potential therapeutic targets for cancer therapy. Finally, we introduced several emerging technologies that can be utilized to develop effective therapeutic agents for targeting tumor microenvironment.
Highlights
Ubiquitination is a dynamic and finely regulated post-translational modification pathway that is involved in numerous critical cellular processes, such as selective autophagy [1], the DNA damage response [2] and the innate immune response [3]
DUBs are classified into six families based on conserved catalytic domains: ubiquitin-specific proteases (USPs), ubiquitin Cterminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Machado-Joseph disease proteases (MJDs), JAB1/MPR/Mov34 metalloproteases (JAMMs) and motif interacting with ubiquitin-containing novel DUB family (MINDY) [7,8]
It is conceivable that this technology can be applied to develop potent modulators of E3s and DUBs related to tumor microenvironment (TME) components as novel therapeutics for cancer treatment.1B4eolfo2w6, we briefly introduce several examples of how ubiquitin variants (UbVs) can be developed to modulate the catalytic activity of DUBs and E3 ligases (Figure 7)
Summary
Ubiquitination is a dynamic and finely regulated post-translational modification pathway that is involved in numerous critical cellular processes, such as selective autophagy [1], the DNA damage response [2] and the innate immune response [3]. This process attaches a small protein called ubiquitin (76 aa, ~8.5 kDa, named after its ubiquitous presence in cells) to substrate proteins through a sequential catalysis pathway involving E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases (Figure 1).
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