title: Trim58 degrades Dynein and regulates terminal erythropoiesis.
abstract: TRIM58 is an E3 ubiquitin ligase superfamily member implicated by genome-wide association studies to regulate human erythrocyte traits. Here, we show that Trim58 expression is induced during late erythropoiesis and that its depletion by small hairpin RNAs (shRNAs) inhibits the maturation of late-stage nucleated erythroblasts to anucleate reticulocytes. Imaging flow cytometry studies demonstrate that Trim58 regulates polarization and/or extrusion of erythroblast nuclei. In vitro, Trim58 directly binds and ubiquitinates the intermediate chain of the microtubule motor dynein. In cells, Trim58 stimulates proteasome-dependent degradation of the dynein holoprotein complex. During erythropoiesis, Trim58 expression, dynein loss, and enucleation occur concomitantly, and all are inhibited by Trim58 shRNAs. Dynein regulates nuclear positioning and microtubule organization, both of which undergo dramatic changes during erythroblast enucleation. Thus, we propose that Trim58 promotes this process by eliminating dynein. Our findings identify an erythroid-specific regulator of enucleation and elucidate a previously unrecognized mechanism for controlling dynein activity.
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Thom
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Traxler
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Khandros
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Nickas
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Olivia Y
authors.initials: OY
authors.lastname: Zhou
authors.affiliation: Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Lazarus
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Ana P G
authors.initials: AP
authors.lastname: Silva
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Dolly
authors.initials: D
authors.lastname: Prabhu
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Chiaka
authors.initials: C
authors.lastname: Aribeana
authors.affiliation: Department of Animal Biology and Mari Lowe Comparative Oncology Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: mitch.weiss@stjude.org.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D004398:Dyneins / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis; D051379:Mice; D011485:Protein Binding; D012156:Reticulocytes / Q000166:cytology / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000070584:Tripartite Motif Proteins; C000593618:Trim58 protein, mouse; D044767:Ubiquitin-Protein Ligases; D004398:Dyneins