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Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria

Sara Al Rawi, Lorna Simpson, View ORCID ProfileNeil Q. McDonald, Veronika Chernuha, Orly Elpeleg, Massimo Zeviani, Roger A. Barker, Ronen Spiegel, View ORCID ProfileHeike Laman
doi: https://doi.org/10.1101/2021.12.22.473884
Sara Al Rawi
1University of Cambridge, Department of Pathology, Tennis Court Road, CB2 1QP
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Lorna Simpson
1University of Cambridge, Department of Pathology, Tennis Court Road, CB2 1QP
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Neil Q. McDonald
2Signalling and Structural Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT and also Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, WC1E 7HX, UK
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  • ORCID record for Neil Q. McDonald
Veronika Chernuha
3Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Medical Centre and Sackler Faculty of Medicine, Tel Aviv, Israel
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Orly Elpeleg
4Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Massimo Zeviani
5Mitochondrial Biology Unit, The MRC and University of Cambridge, Cambridge CB2 0XY, UK. Department of Neurosciences, University of Padova, 35128 Padova, Italy
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Roger A. Barker
6John van Geest Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY 0PY and Wellcome-MRC Cambridge Stem Cell Institute
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Ronen Spiegel
7Pediatric Department, Emek Medical Center, Afula 18101, Israel
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Heike Laman
1University of Cambridge, Department of Pathology, Tennis Court Road, CB2 1QP
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  • ORCID record for Heike Laman
  • For correspondence: hl316@cam.ac.uk
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Abstract

Mutations in FBXO7 have been discovered associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerization domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, L250P patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts directly with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts as an adaptor enabling SCFFbxo7 ligase to ubiquitinate MiD49. Thus, the L250P mutation changes the function of Fbxo7 by altering its substrate repertoire. Although MiD49/51 expression was reduced in L250P patient cells, there was no effect on the mitochondrial network. However, patient cells had higher levels of ROS and reduced viability under stress. Our study shows that Fbxo7 and PI31 affect each other’s functions in regulating both proteasomal and mitochondrial function and demonstrate a new function for PI31, as an adaptor for the SCFFbxo7 E3 ubiquitin ligase.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵^ Co-senior author

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 4.0 International license.
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Posted December 23, 2021.
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Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria
Sara Al Rawi, Lorna Simpson, Neil Q. McDonald, Veronika Chernuha, Orly Elpeleg, Massimo Zeviani, Roger A. Barker, Ronen Spiegel, Heike Laman
bioRxiv 2021.12.22.473884; doi: https://doi.org/10.1101/2021.12.22.473884
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Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria
Sara Al Rawi, Lorna Simpson, Neil Q. McDonald, Veronika Chernuha, Orly Elpeleg, Massimo Zeviani, Roger A. Barker, Ronen Spiegel, Heike Laman
bioRxiv 2021.12.22.473884; doi: https://doi.org/10.1101/2021.12.22.473884

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