Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function
Sameer Ahmed Bhat,
Zahra Vasi,
Liping Jiang,
Shruthi Selvaraj,
Rachel Ferguson,
Sanaz Salarvand,
Anish Gudur,
Ritika Adhikari,
Veronica Castillo,
Hagar Ismail,
Avantika Dhabaria,
Beatrix Ueberheide,
Shafi Kuchay
Affiliations
Sameer Ahmed Bhat
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Zahra Vasi
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Liping Jiang
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Shruthi Selvaraj
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Rachel Ferguson
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Sanaz Salarvand
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Anish Gudur
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Ritika Adhikari
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Veronica Castillo
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Hagar Ismail
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA
Avantika Dhabaria
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10013, USA
Beatrix Ueberheide
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10013, USA
Shafi Kuchay
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, MBRB 1252, Chicago, IL 60607, USA; Cancer Center, University of Illinois at Chicago, Chicago, IL, USA; Corresponding author
Summary: Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.
