Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit.
Little is known about the role of protein quality control in the inner ear. We now report selective cochlear degeneration in mice deficient in Fbx2, a ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins (Yoshida et al., 2002). Originally described as a brain-enriched protein (Erhardt et al., 1998), Fbx2 is also highly expressed in the organ of Corti, in which it has been called organ of Corti protein 1 (Thalmann et al., 1997). Mice with targeted deletion of Fbxo2 develop age-related hearing loss beginning at 2 months. Cellular degeneration begins in the epithelial support cells of the organ of Corti and is accompanied by changes in cellular membrane integrity and early increases in connexin 26, a cochlear gap junction protein previously shown to interact with Fbx2 (Henzl et al., 2004). Progressive degeneration includes hair cells and the spiral ganglion, but the brain itself is spared despite widespread CNS expression of Fbx2. Cochlear Fbx2 binds Skp1, the common binding partner for F-box proteins, and is an unusually abundant inner ear protein. Whereas cochlear Skp1 levels fall in parallel with the loss of Fbx2, other components of the canonical SCF (Skp1, Cullin1, F-box, Rbx1) ubiquitin ligase complex remain unchanged and show little if any complex formation with Fbx2/Skp1, suggesting that cochlear Fbx2 and Skp1 form a novel, heterodimeric complex. Our findings demonstrate that components of protein quality control are essential for inner ear homeostasis and implicate Fbx2 and Skp1 as potential genetic modifiers in age-related hearing loss.
Nelson
Rick F
RF
Medical Scientist Training Program, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
Glenn
Kevin A
KA
Zhang
Yuzhou
Y
Wen
Hsiang
H
Knutson
Tina
T
Gouvion
Cynthia M
CM
Robinson
Barbara K
BK
Zhou
Zouping
Z
Yang
Baoli
B
Smith
Richard J H
RJ
Paulson
Henry L
HL
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015834:Cochlear Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003638:Deafness / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D044783:F-Box Proteins / Q000235:genetics*; D006023:Glycoproteins / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007760:Labyrinth Supporting Cells / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism
D017630:Connexins; D044783:F-Box Proteins; C500719:Fbx2 protein, mouse; C000607043:Gjb2 protein, mouse; D006023:Glycoproteins; D046911:Macromolecular Substances; D021122:Protein Subunits; D000072259:Connexin 26; D043743:Ubiquitin-Protein Ligase Complexes; D044843:SKP Cullin F-Box Protein Ligases