GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:29689197

From GONUTS
Jump to: navigation, search
Citation

Tan, KL, Haelterman, NA, Kwartler, CS, Regalado, ES, Lee, PT, Nagarkar-Jaiswal, S, Guo, DC, Duraine, L, Wangler, MF, University of Washington Center for Mendelian Genomics, Bamshad, MJ, Nickerson, DA, Lin, G, Milewicz, DM and Bellen, HJ (2018) Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms. Dev. Cell 45:226-244.e8

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.

Links

PubMed PMC5920516 Online version:10.1016/j.devcel.2018.03.020

Keywords

Adolescent; Adult; Aged; Aged, 80 and over; Animals; Aortic Aneurysm/genetics; Aortic Aneurysm/metabolism; Aortic Aneurysm/pathology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Nucleus/genetics; Cell Nucleus/metabolism; Cell Nucleus/pathology; Child, Preschool; Cytoskeleton; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/growth & development; Drosophila melanogaster/metabolism; Female; Humans; Male; Middle Aged; Mutation; Myocytes, Smooth Muscle/metabolism; Myocytes, Smooth Muscle/pathology; Pedigree; Phenotype; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Young Adult

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:A0A0B4KEE4

located_in

GO:0005635: nuclear envelope

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4KEE4

involved_in

GO:0051647: nucleus localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:M9MRJ4

involved_in

GO:0051647: nucleus localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:UBC10

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0017418

F

Seeded From UniProt

complete

DROME:PRKN

involved_in

GO:0006513: protein monoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:ARI1

enables

GO:0031624: ubiquitin conjugating enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0026316

F

Seeded From UniProt

complete

DROME:ARI1

involved_in

GO:0006513: protein monoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:ARI1

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:ARI1

involved_in

GO:1901800: positive regulation of proteasomal protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0006513: protein monoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

enables

GO:0042803: protein homodimerization activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.