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

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.

The number of growing microtubules and nucleus-nucleus interactions uniquely regulate nuclear movement inDrosophilamuscle

“…Several microtubule associated genes including ensconsin/MAP7 (Metzger et al, 2012), Bsg25D/Ninein (Rosen et al, 2019), and the motors kinesin and cytoplasmic dynein (Folker et al, 2012, 2014) have been suggested to contribute to nuclear movement by regulating Kinesin activity (Metzger et al, 2012), microtubule stability (Rosen et al, 2019), and the application of force both directly on (Folker et al, 2014) and at a distance from (Folker et al, 2012). Similar experiments have shown that the LINC complex components klarsicht, (Elhanany-Tamir et al, 2012; Collins & Mandigo et al, 2017), Msp300 (Elhanany-Tamir et al, 2012), and klaroid (Tan et al, 2018) along with the emerin homologs bocksbeutel and Otefin (Collins & Mandigo et al, 2017; Mandigo et al, 2019) are also critical for nuclear positioning during muscle development. Despite identifying many of the factors that are critical for nuclear position, we know little about the mechanisms by which they support nuclear movement during muscle development.…”

Loss-of-function in IRF2BPL is associated with neurological phenotypes

“…To validate the functional consequences of these variants, we utilized Drosophila melanogaster as a model organism. Experiments in fruit flies have previously provided experimental support in identifying causal variants for human disease 19,53-55 and these approaches have been an integral part of the UDN. 13,14,16,21,56 The fly ortholog of IRF2BPL is a poorly characterized gene, CG11138 .…”

A Newly Discovered Genetic Disorder Associated With Life-Threatening Aortic Disease in a 6-Year-Old Boy

“…Tan et al report that mutations of ari-1 in Drosophila are responsible for the clustering of nuclei in striatal muscle as compared with the wild-type larvae. 4 Following this discovery, the patient was 1 of 3 who was found to have a rare variant of ARIH1 gene. ARIH1 variants expressed in Drosophila showed failure in rescuing nuclear positioning of ari-1 mutants and did not survive for more than a few days, concluding that variants result in loss of function of ARIH1 protein.…”