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

TitleAri-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms.
Publication TypeJournal Article
Year of Publication2018
AuthorsTan, KLi, Haelterman, NA, Kwartler, CS, Regalado, ES, Lee, P-T, Nagarkar-Jaiswal, S, Guo, D-C, Duraine, L, Wangler, MF, Bamshad, MJ, Nickerson, DA, Lin, G, Milewicz, DM, Bellen, HJ
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalDev Cell
Date Published2018 04 23
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Animals, Aortic Aneurysm, Carrier Proteins, Cell Nucleus, Child, Preschool, Cytoskeleton, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Male, Middle Aged, Mutation, Myocytes, Smooth Muscle, Pedigree, Phenotype, Ubiquitin-Protein Ligases, Young Adult

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.

Alternate JournalDev. Cell
PubMed ID29689197
PubMed Central IDPMC5920516
Grant ListP40 OD018537 / OD / NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
R01 GM067858 / GM / NIGMS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R24 OD022005 / OD / NIH HHS / United States
P01 HL110869 / HL / NHLBI NIH HHS / United States
R01 HL109942 / HL / NHLBI NIH HHS / United States