title: O-GlcNAc regulates NEDD4-1 stability via caspase-mediated pathway.
abstract: O-GlcNAc modification of cytosolic and nuclear proteins regulates essential cellular processes such as stress responses, transcription, translation, and protein degradation. Emerging evidence indicates O-GlcNAcylation has a dynamic interplay with ubiquitination in cellular regulation. Here, we report that O-GlcNAc indirectly targets a vital E3 ubiquitin ligase enzyme of NEDD4-1. The protein level of NEDD4-1 is accordingly decreased following an increase of overall O-GlcNAc level upon PUGNAc or glucosamine stimulation. O-GlcNAc transferase (OGT) knockdown, overexpression and mutation results confirm that the stability of NEDD4-1 is negatively regulated by cellular O-GlcNAc. Moreover, the NEDD4-1 degradation induced by PUGNAc or GlcN is significantly inhibited by the caspase inhibitor. Our study reveals a regulation mechanism of NEDD4-1 stability by O-GlcNAcylation.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
authors.forename: Kuan
authors.initials: K
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
authors.forename: Bingyang
authors.initials: B
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Ta
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
authors.forename: Tingling
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China.
authors.forename: Zikang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China. Electronic address: pwang@nankai.edu.cn.
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Collaborative Innovation Center for Biotherapy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300071, China. Electronic address: lianwen@nankai.edu.cn.
authors.forename: Lianwen
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000215:Acylation; D020169:Caspases / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D010091:Oximes / Q000378:metabolism*; D048448:Phenylcarbamates / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D020169:Caspases; D000117:Acetylglucosamine
keywords: Caspase; NEDD4-1; O-GlcNAcylation; OGT