title: Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing.
abstract: The mechanisms controlling the steady-state cell surface levels of cytokine receptors, and consequently the cellular response to cytokines, remain poorly understood. The number of surface-exposed receptors is a dynamic balance of de novo synthesis, transport to the plasma membrane, internalization, recycling, degradation and ectodomain shedding. We previously reported that the E3 ubiquitin ligase RING finger protein 41 (RNF41) inhibits basal lysosomal degradation and enhances ectodomain shedding of JAK2-associated cytokine receptors. Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins. The present study identifies USP8 as a substrate of RNF41 and reveals that loss of USP8 explains the aforementioned RNF41 effects. RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels. In addition, USP8 knockdown functionally matches the effects of RNF41 ectopic expression on the model leptin and leukemia inhibitory factor (LIF) receptors. Moreover, RNF41 indirectly destabilizes the ESCRT-0 complex through suppression of USP8. Collectively, our findings demonstrate that RNF41 controls JAK2-associated cytokine receptor trafficking by acting as a key regulator of USP8 and ESCRT-0 stability. Balanced reciprocal cross-regulation of RNF41 and USP8 thus determines whether receptors are sorted for lysosomal degradation or recycling, this way regulating basal cytokine receptor levels.
authors.affiliation: Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
authors.forename: Leentje
authors.initials: L
authors.lastname: De Ceuninck
authors.forename: Joris
authors.initials: J
authors.lastname: Wauman
authors.forename: Delphine
authors.initials: D
authors.lastname: Masschaele
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
mesh_terms: D002465:Cell Movement / Q000502:physiology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D018121:Receptors, Cytokine; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Cathepsin-L cleavage; Ectodomain shedding; Nrdp1; RNF41; Type 1 cytokine receptor; USP8