title: Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1α in hypoxic cardiomyocytes.
abstract: Our previous study suggested that microtubule network alteration affects the process of glycolysis in cardiomyocytes (CMs) via the regulation of hypoxia-inducible factor (HIF)-1α during the early stages of hypoxia. However, little is known regarding the underlying mechanisms of microtubule network alteration-induced changes of HIF-1α. The von Hippel-Lindau tumor suppressor protein (pVHL) has been shown to mediate the ubiquitination of HIF-1α in the nuclear compartment prior to HIF-1α exportation to the cytoplasm, and pVHL dynamic nuclear-cytoplasmic trafficking is indicated to be involved in the process of HIF-1α degradation. In this study, by administering different microtubule-stabilizing and -depolymerizing interventions, we demonstrated that microtubule stabilization promoted pVHL nuclear export and drove the translocation of pVHL to the cytoplasm, while microtubule disruption prevented pVHL nuclear export in hypoxic CMs. Moreover, the ratio between nuclear and cytoplasmic pVHL was associated with HIF-1α regulation. Importantly, microtubule network alteration also affected the subcellular localization of Ran, which was involved in the regulation of pVHL nuclear-cytoplasmic trafficking. The above results suggest that the subcellular translocation of pVHL plays an important role in microtubular structure alteration-induced HIF-1α regulation. Interestingly, Ran is involved in the process of pVHL nuclear-cytoplasmic trafficking following microtubule network alteration in hypoxic CMs.
authors.affiliation: 1] Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, China [2] Department of Burn and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xupin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Hengshu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Teng
mesh_terms: D000818:Animals; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D051381:Rats; D014404:Tubulin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014404:Tubulin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D020931:ran GTP-Binding Protein