Abstract
The Cullin2-type ubiquitin ligases belong to the Cullin-Ring Ligase (CRL) family, which is a crucial determinant of proteasome-based degradation processes in eukaryotes. Because of the finding of von Hippel-Lindau tumor suppressor (VHL), the Cullin2-type ubiquitin ligases gain focusing in the research of many diseases, especially in tumors. These multisubunit enzymes are composed of the Ring finger protein, the Cullin2 scaffold protein, the Elongin B&C linker protein and the variant substrate recognition subunits (SRSs), among which the Cullin2 scaffold protein is the determining factor of the enzyme mechanism. Substrate recognition of Cullin2-type ubiquitin ligases depends on SRSs and results in the degradation of diseases associated substrates by intracellular signaling events. This review focuses on the diversity and the multifunctionality of SRSs in the Cullin2-type ubiquitin ligases, including VHL, LRR-1, FEM1b, PRAME and ZYG11. Recently, as more SRSs are being discovered and more aspects of substrate recognition have been illuminated, insight into the relationship between Cul2-dependent SRSs and substrates provides a new area for cancer research.
Highlights
Ubiquitin-proteasome systemThe ubiquitin-proteasome system is a crucial determinant of virtually all biological processes in eukaryotes and has emerged as a central mechanism to regulate protein turnover spatially and temporally [1, 2]
The Cullin2-type ubiquitin ligases belong to the Cullin-Ring Ligase (CRL) family, which is a crucial determinant of proteasome-based degradation processes in eukaryotes
Given the importance of Cullin2, there have been five confirmed Cul2-dependent substrate recognition subunits (SRSs) discovered in succession during the past decades: the von Hippel-Lindau (VHL) tumor suppressor, which degrades hypoxia-inducible factor-α (HIF-α) under normoxic conditions [22]; LRR1, which was first found to suppress 4-1-BB receptor signaling in CD4+ and CD8+ T cells [23], and found to act as a SRS of Cullin2-type ubiquitin ligase [24]; FEM1b, which regulates glucose-stimulated insulin secretion [25]; preferentially expressed antigen of melanoma (PRAME), which is a transcription factor essential for early embryonic development that is confirmed to be enriched at enhancers and at transcriptionally active promoters [26]; and ZYG11, which was found to act as a cell-cycle regulator in Caenorhabditis elegans [27]
Summary
The ubiquitin-proteasome system is a crucial determinant of virtually all biological processes in eukaryotes and has emerged as a central mechanism to regulate protein turnover spatially and temporally [1, 2]. Given the importance of Cullin, there have been five confirmed Cul2-dependent SRSs discovered in succession during the past decades: the von Hippel-Lindau (VHL) tumor suppressor, which degrades hypoxia-inducible factor-α (HIF-α) under normoxic conditions [22]; LRR1, which was first found to suppress 4-1-BB receptor signaling in CD4+ and CD8+ T cells [23], and found to act as a SRS of Cullin2-type ubiquitin ligase [24]; FEM1b, which regulates glucose-stimulated insulin secretion [25]; PRAME, which is a transcription factor essential for early embryonic development that is confirmed to be enriched at enhancers and at transcriptionally active promoters [26]; and ZYG11, which was found to act as a cell-cycle regulator in Caenorhabditis elegans [27]. The latest research indicates that ZYG11A may serve as a novel oncogene promoting tumorigenicity of NSCLC cells by inducing cell cycle alterations and increasing CCNE1 expression [28]
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