2. Academic Validation
  3. Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms

Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms

  • Dev Cell. 2018 Apr 23;45(2):226-244.e8. doi: 10.1016/j.devcel.2018.03.020.
Kai Li Tan 1,  Nele A Haelterman 2,  Callie S Kwartler 3,  Ellen S Regalado 3,  Pei-Tseng Lee 4,  Sonal Nagarkar-Jaiswal 5,  Dong-Chuan Guo 3,  Lita Duraine 6,  Michael F Wangler 2,  University of Washington Center for Mendelian Genomics 7,  Michael J Bamshad 8,  Deborah A Nickerson 8,  Guang Lin 4,  Dianna M Milewicz 3,  Hugo J Bellen 9
Affiliations

Affiliations

  • 1 Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
  • 2 Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
  • 3 Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
  • 4 Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
  • 5 Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA.
  • 6 Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA.
  • 7 University of Washington, Seattle, WA 98195, USA.
  • 8 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 9 Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 29689197 DOI: 10.1016/j.devcel.2018.03.020
Abstract

Nuclei are actively positioned and anchored to the Cytoskeleton via the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We identified mutations in the Parkin-like E3 ubiquitin ligase Ariadne-1 (Ari-1) that affect the localization and distribution of LINC complex members in Drosophila. ari-1 mutants exhibit nuclear clustering and morphology defects in larval muscles. We show that Ari-1 mono-ubiquitinates the core LINC complex member Koi. Surprisingly, we discovered functional redundancy between Parkin and Ari-1: increasing Parkin expression rescues ari-1 mutant phenotypes and vice versa. We further show that rare variants in the human homolog of ari-1 (ARIH1) are associated with thoracic aortic aneurysms and dissections, conditions resulting from smooth muscle cell (SMC) dysfunction. Human ARIH1 rescues fly ari-1 mutant phenotypes, whereas human variants found in patients fail to do so. In addition, SMCs obtained from patients display aberrant nuclear morphology. Hence, ARIH1 is critical in anchoring myonuclei to the Cytoskeleton.

Keywords

ARIH1; Drosophila; MSP300; SUN proteins; aortic dissection; cerebrovascular aneurysm; koi; linker of nuclear skeleton and cytoskeleton (LINC); nuclear envelope; ring in between ring E3 ligases.

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