Abstract
In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.
Highlights
IntroductionStudies described the ability of 14-3-3 proteins to form homo- or hetero-dimeric complexes and numerous reports of new binding partners confirmed their chaperone activity.[2,3] This highly conserved family of small 28–33 kDa acidic dimeric proteins consists of seven distinct subunit isoforms (β, ε, γ, η, τ, σ and ζ) encoded by seven genes named YWHAx, (x being either B, E, G, H, Q, S or Z).[4] These proteins mostly bind serine/threonine phosphorylated ligands altering their sub-cellular localization, stability, phosphorylation state, activity or molecular interactions with other targets, controlling cell cycle and many signal transduction pathways.[2,3] A primary function of 14-3-3 proteins is the inhibition of apoptosis by retaining pro-apoptotic factors such as Bad or Bax in the cytoplasm.[5,6,7 -3] proteins were originally discovered as abundant molecules in the brain,[8] and follow-up studies confirmed that the highest tissue concentration of 14-3-3 proteins is in the brain,[9] comprising about 1% of total proteins of the brain
The 14-3-3 proteins were initially described as tyrosine3-monooxygenase/tryptophan 5-monooxygenase activation proteins (YWHAx) required for the synthesis of neurotransmitters (dopamine, adrenaline, serotonin) from catecholamine.[1]Subsequently, studies described the ability of 14-3-3 proteins to form homo- or hetero-dimeric complexes and numerous reports of new binding partners confirmed their chaperone activity.[2,3] This highly conserved family of small 28–33 kDa acidic dimeric proteins consists of seven distinct subunit isoforms (β, ε, γ, η, τ, σ and ζ) encoded by seven genes named YWHAx, (x being either B, E, G, H, Q, S or Z).[4]
In the peripheral nervous system, proteomics experiments showed that 14-3-3 proteins were expressed in the cochlea,[10,11,12] and among the seven 14-3-3 isoforms, 14-3-3eta encoded by the YWHAH gene has been found highly expressed in retinal ganglion cells (RGC).[13]
Summary
Studies described the ability of 14-3-3 proteins to form homo- or hetero-dimeric complexes and numerous reports of new binding partners confirmed their chaperone activity.[2,3] This highly conserved family of small 28–33 kDa acidic dimeric proteins consists of seven distinct subunit isoforms (β, ε, γ, η, τ, σ and ζ) encoded by seven genes named YWHAx, (x being either B, E, G, H, Q, S or Z).[4] These proteins mostly bind serine/threonine phosphorylated ligands altering their sub-cellular localization, stability, phosphorylation state, activity or molecular interactions with other targets, controlling cell cycle and many signal transduction pathways.[2,3] A primary function of 14-3-3 proteins is the inhibition of apoptosis by retaining pro-apoptotic factors such as Bad or Bax in the cytoplasm.[5,6,7 -3] proteins were originally discovered as abundant molecules in the brain,[8] and follow-up studies confirmed that the highest tissue concentration of 14-3-3 proteins is in the brain,[9] comprising about 1% of total proteins of the brain. We have investigated the function of 14-3-3eta in both auditory and visual systems, and we report that the loss of 14-3-3eta protein is associated with cochlear hair cells' degeneration
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