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Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.
Al Rawi, Sara; Simpson, Lorna; Agnarsdóttir, Guðrún; McDonald, Neil Q; Chernuha, Veronika; Elpeleg, Orly; Zeviani, Massimo; Barker, Roger A; Spiegel, Ronen; Laman, Heike.
Afiliación
  • Al Rawi S; Department of Pathology, University of Cambridge, UK.
  • Simpson L; Department of Pathology, University of Cambridge, UK.
  • Agnarsdóttir G; Department of Pathology, University of Cambridge, UK.
  • McDonald NQ; Signalling and Structural Biology Laboratory, The Francis Crick Institute, London, UK.
  • Chernuha V; Department of Biological Sciences, Institute of Structural and Molecular Biology, London, UK.
  • Elpeleg O; Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Medical Centre and Sackler Faculty of Medicine, Israel.
  • Zeviani M; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Barker RA; Mitochondrial Biology Unit, The MRC and University of Cambridge, UK.
  • Spiegel R; John van Geest Centre for Brain Repair, Cambridge, UK.
  • Laman H; Wellcome-MRC Cambridge Stem Cell Institute, UK.
FEBS J ; 291(12): 2565-2589, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38466799
ABSTRACT
Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation 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, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCFFbxo7-mediated ubiquitination of MiD49. The L250P mutation reduces the SCFFbxo7 ligase-mediated ubiquitination of a subset of its known substrates. Although MiD49/51 expression was reduced in patient cells, there was no effect on the mitochondrial network. However, patient cells show reduced levels of mitochondrial function and mitophagy, higher levels of ROS and are less viable under stress. Our study demonstrates that Fbxo7 and PI31 regulate proteasomes and mitochondria and reveals a new function for PI31 in enhancing the SCFFbxo7 E3 ubiquitin ligase activity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas F-Box / Complejo de la Endopetidasa Proteasomal / Ubiquitinación / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas F-Box / Complejo de la Endopetidasa Proteasomal / Ubiquitinación / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido