Abstract
Cullin-RING ubiquitin ligases are the largest Ubiquitin ligase family in eukaryotes and are multi-protein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. KLHL20 is a substrate-binding subunit of Cullin3 (Cul3) ubiquitin ligase. Recent studies have identified a number of substrates of KLHL20-based ubiquitin ligase. Through ubiquitination of these substrates, KLHL20 elicits diverse cellular functions, some of which are associated with human diseases. Furthermore, the functions, subcellular localizations, and expression of KLHL20 are regulated by several physiological and stressed signals, which allow KLHL20 to preferentially act on certain substrates to response to these signals. Here, we provide a summary of the functions and regulations of KLHL20 in several physiological processes and stress responses and its disease implications.
Highlights
Protein ubiquitination regulates a broad range of physiological processes and disease conditions
Cullin-RING multi-protein complexes comprise the largest family of ubiquitin ligases, in which one particular Cullin serves as a scaffold for linking two functional modules: the catalytic RING finger protein Rbx1 or Roc2 and the substrate-binding module for bringing substrate within the proximity to the catalytic module [5]
In addition to promoting cell death, death-associated protein kinase (DAPK) elicits other anti-cancer functions, such as suppression of metastasis by regulating cell migration, adhesion, and cytoskeleton remodeling [32, 38,39,40] and inhibition of cell transformation by inactivating the phospho-Ser/Thr directed isomerase Pin1 [41]. In line with these tumor suppressive functions, DAPK expression or activity is Interestingly, the Cul3-KLHL20-mediated DAPK ubiquitination and degradation is blocked in response to IFN-α or IFN-γ treatment, which provides an explanation for an important role of DAPK in apoptotic and autophagic death induced by these stimuli
Summary
Protein ubiquitination regulates a broad range of physiological processes and disease conditions. KLHL20 was discovered before the identification of a functional link of BTB-kelch proteins to Cul3 ubiquitin ligases. Regulation of cell death The first substrate identified for Cul3-KLHL20 ubiquitin ligase is death-associated protein kinase (DAPK).
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