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Moyamoya Disease-Associated RNF213 Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation

Abhishek Bhardwaj, Robert S. Banh, Wei Zhang, Sachdev S. Sidhu, Benjamin G. Neel
doi: https://doi.org/10.1101/2020.05.24.113795
Abhishek Bhardwaj
1Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA
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Robert S. Banh
1Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA
2Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada
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Wei Zhang
3Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
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Sachdev S. Sidhu
3Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
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Benjamin G. Neel
1Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA
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  • For correspondence: Benjamin.Neel@nyulangone.org
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Abstract

Single nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591kDa protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, Moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily be explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3-ligase activity have remained unclear. We found that the RING domain of RNF213 uses the E2-conjugating enzyme UBE2D2 to catalyze predominantly K6-dependent poly-ubiquitination events comprising a mixture of typical and atypical ubiquitin linkages. MMD-associated SNPs encode proteins with decreased E3-ligase activity and the most frequent MMD allele, RNF213R4810K, is a dominant negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated RNF213 SNPs do not affect ATPase activity. We propose that decreased RNF213 E3-ligase activity is central to MMD pathogenesis.

Competing Interest Statement

B.G.N. is a co-founder, has equity in, and receives consulting revenue from Northern Biologics and Navire Pharmaceuticals. He is a member of the SAB, holds equity in, and receives consulting fees from Arvinas, Inc. He is an expert witness for Johnson and Johnson in the ovarian cancer talc litigation in US Federal Court. His spouse holds equity in Arvinas, Inc, Amgen, Gilead, and Regeneron. None of these interests is directly relevant to the work herein.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 26, 2020.
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Moyamoya Disease-Associated RNF213 Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation
Abhishek Bhardwaj, Robert S. Banh, Wei Zhang, Sachdev S. Sidhu, Benjamin G. Neel
bioRxiv 2020.05.24.113795; doi: https://doi.org/10.1101/2020.05.24.113795
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Moyamoya Disease-Associated RNF213 Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation
Abhishek Bhardwaj, Robert S. Banh, Wei Zhang, Sachdev S. Sidhu, Benjamin G. Neel
bioRxiv 2020.05.24.113795; doi: https://doi.org/10.1101/2020.05.24.113795

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