Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cyclic AMP-regulated chloride channel that plays an important role in regulating the volume of the lung airway surface liquid, and thereby mucociliary clearance and elimination of pathogens from the lung. In epithelial cells, cell surface CFTR abundance is determined in part by regulating both CFTR endocytosis from the apical plasma membrane and recycling back to the plasma membrane. We recently reported, using an activity-based chemical screen to identify active deubiquitinating enzymes (DUBs) in human airway epithelial cells, that Ubiquitin Specific Protease-10 (USP10) is located and active in the early endosomal compartment and regulates the deubiquitination of CFTR and thereby promotes its endocytic recycling. siRNA-mediated knockdown of USP10 increased the multi-ubiquitination and lysosomal degradation of CFTR and decreased the endocytic recycling and the half-life of CFTR in the apical membrane, as well as CFTR-mediated chloride secretion. Overexpression of wild-type USP10 reduced CFTR multi-ubiquitination and degradation, while overexpression of a dominant-negative USP10 promoted increased multi-ubiquitination and lysosomal degradation of CFTR. In the current study, we show localization and activity of USP10 in the early endosomal compartment of primary bronchial epithelial cells, as well as an interaction between CFTR and USP10 in this compartment. These studies demonstrate a novel function for USP10 in facilitating the deubiquitination of CFTR in early endosomes, thereby enhancing the endocytic recycling and cell surface expression of CFTR.
Channels (Austin)
PMID:The deubiquitinating enzyme USP10 regulates the endocytic recycling of CFTR in airway epithelial cells. 2021 69

Posttranscriptional modifications of proteins by the ubiquitin and SUMO (Small Ubiquitin-related Modifier) pathways regulate the function of protein networks, enable cells to respond to signaling cues during development, and to cope with the changing environment during adult life. Both modifications can impact protein stability, localization, protein-protein interactions and/or function. While both pathways have been well studied individually, the long-speculated nature of crosstalk between SUMO and ubiquitin pathways has been molecularly enigmatic. Recent work in yeast and mammalian cells identified the connection between the two pathways in the form of a conserved family of RING finger ubiquitin ligases termed SUMO-Targeted ubiquitin ligases (STUbLs). These proteins bind to SUMOylated substrates via their SUMO interaction motif and subsequently target them for ubiquitylation. Characterization of Degringolade (Dgrn), a STUbL gene in the fly genome, enabled us to evaluate the contribution of STUbLs to the development of multi-cellular organisms. Analysis of dgrn mutants showed that they are required for cyto-nuclear organization during early embryonic development, and are likely required to cope with mitotic stress and DNA damage. Furthermore, in transcription, STUbLs regulate protein-protein interactions, and are part of molecular machinery that regulates co-repressor choice and gene-expression selectivity during development.
Fly (Austin)
PMID:A fly view of a SUMO-targeted ubiquitin ligase. 2185 64