title: The X-Linked-Intellectual-Disability-Associated Ubiquitin Ligase Mid2 Interacts with Astrin and Regulates Astrin Levels to Promote Cell Division.
abstract: Mid1 and Mid2 are ubiquitin ligases that regulate microtubule dynamics and whose mutation is associated with X-linked developmental disorders. We show that astrin, a microtubule-organizing protein, co-purifies with Mid1 and Mid2, has an overlapping localization with Mid1 and Mid2 at intercellular bridge microtubules, is ubiquitinated by Mid2 on lysine 409, and is degraded during cytokinesis. Mid2 depletion led to astrin stabilization during cytokinesis, cytokinetic defects, multinucleated cells, and cell death. Similarly, expression of a K409A mutant astrin in astrin-depleted cells led to the accumulation of K409A on intercellular bridge microtubules and an increase in cytokinetic defects, multinucleated cells, and cell death. These results indicate that Mid2 regulates cell division through the ubiquitination of astrin on K409, which is critical for its degradation and proper cytokinesis. These results could help explain how mutation of MID2 leads to misregulation of microtubule organization and the downstream disease pathology associated with X-linked intellectual disabilities.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ankur A
authors.initials: AA
authors.lastname: Gholkar
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Senese
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lo
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Edmundo
authors.initials: E
authors.lastname: Vides
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ely
authors.initials: E
authors.lastname: Contreras
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Hodara
authors.affiliation: Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Capri
authors.affiliation: Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: torres@chem.ucla.edu.
authors.forename: Jorge Z
authors.initials: JZ
authors.lastname: Torres
mesh_terms: D000423:Alcian Blue / Q000378:metabolism*; D002455:Cell Division; D048749:Cytokinesis; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D010619:Phenazines / Q000378:metabolism*; D010640:Phenothiazines / Q000378:metabolism*; D012118:Resorcinols / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C121118:MID2 protein, human; D008869:Microtubule-Associated Proteins; D010619:Phenazines; D010640:Phenothiazines; D012118:Resorcinols; D014157:Transcription Factors; D025801:Ubiquitin; C034790:astrin; D008025:Ligases; D000423:Alcian Blue
keywords: Mid2; X-linked intellectual disability; astrin; cell division; cytokinesis