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The role of post-translational modifications in hearing and deafness

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Abstract

Post-translational modifications (PTMs) are key molecular events that modify proteins after their synthesis and modulate their ultimate functional properties by affecting their stability, localisation, interaction potential or activity. These chemical changes expand the size of the proteome adding diversity to the molecular pathways governing the biological outcome of cells. PTMs are, thus, crucial in regulating a variety of cellular processes such as apoptosis, proliferation and differentiation and have been shown to be instrumental during embryonic development. In addition, alterations in protein PTMs have been implicated in the pathogenesis of many human diseases, including deafness. In this review, we summarize the recent progress made in understanding the roles of PTMs during cochlear development, with particular emphasis on the enzymes driving protein phosphorylation, acetylation, methylation, glycosylation, ubiquitination and SUMOylation. We also discuss how these enzymes may contribute to hearing impairment and deafness.

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Abbreviations

ABR:

Auditory brainstem response

ADP:

Adenosine diphosphate

Ac-CoA:

Acetyl-coenzyme A

ALG10B:

Alpha-1,2-glucosyltransferase

ARHL:

Age-related hearing loss

Atoh1:

Protein atonal homolog 1

ATP:

Adénosine triphosphate

Aos1/Uba2:

Ubiquitin-like 1-activating enzyme E1B

CBP:

CREB-binding protein

CREB:

cAMP-responsive element binding protein

Cx26:

Connexin-26

DFNB61:

Autosomal recessive deafness-61

DNA:

Deoxyribonucleic acid

DUBs:

Deubiquitinating enzymes

E1:

Ubiquitin activating enzyme

E2:

Ubiquitin conjugating enzyme

E3:

Ubiquitin ligase

ERK1/2:

Extracellular signal-regulated kinases 1/2

ERM:

Ezrin, radixin and moesin proteins

Fbx2:

F-Box protein 2 (also called Fbs1 or OCP1)

FGF:

Fibroblast growth factor

GCN5:

General control nonderepressible

GJP2:

Gap junction protein type 2

GPI:

Glycosylphosphatidylinositol

GTP:

Guanosine triphosphate

H3K9:

Histone H3 lysine 9

HCs:

Hair cells

IDH2:

Isocitrate dehydrogenase

IHCs:

Inner hair cells

JAB1:

Jun activation domain-binding protein 1

JAMMs:

JAB1/MPN/MOV34 metalloenzymes

JNK:

c-Jun N-terminal kinase

KATs:

Lysine acetyl-transferases

KDACi:

Lysine deacetylases inhibitors

KDACs:

Lysine deacetylases

KDMs:

Histones lysine demethylation enzymes

KDM4B:

Lysine (K)-specific demethylase 4B (also called jumonjiD2)

LKB1:

Liver serine/threonine kinase B1

MAP3K1:

Mitogen-activated protein kinase kinase kinase 1

MAP3K4:

Mitogen-activated protein kinase kinase kinase 4 (also called MEKK4)

MAP3K7:

Mitogen-activated protein kinase kinase kinase 7 (also called Tak1)

MAPK:

Mitogen-activated protein kinase

MOV34:

Proteasome 26S subunit, non-ATPase 7 (PSMD7)

MPN:

MPR1/PAD1 N-terminal

MPR1:

sigMa 1278b gene for l-proline-analog resistance

mRNA:

Messenger ribonucleic acid

MYST:

Named for the founding members MOZ, YBF2, SAS2 and TIP60

NAD:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate-oxidase

NEDD8:

Neural precursor cell expressed, developmentally down-regulated 8

NF-κB:

Nuclear factor-kappa B

OCP1:

Organ of corti protein 1 (also called Fbs1 or Fbx2)

OHCs:

Outer hair cells

OTUs:

Ovarian tumor proteases

PAD1:

Protein-arginine deiminase 1

PCAF:

p300/CBP-associated factor

PCP:

Planar cell polarity

Pk:

Prickle1

PKMT:

Protein lysine methyl transferases

PRMT:

Protein arginine methyl transferases

PTK7:

Protein tyrosine kinase 7

PTMs:

Post-translational modifications

RhoA Ras:

Homolog gene family, member A

ROCK1/2:

Rho-associated protein kinase 1/2

SAH:

S-Adenosyl homocysteine

SAM:

S-Adenosyl methionine

SCs:

Supporting cells

SCF:

SKP1-cullin-F-box

Scr:

Proto-oncogene tyrosine-protein kinase

SGN:

Spiral ganglion neurons

SLC26A4:

Solute carrier family 26 (anion exchanger), member 4

SLC26A5:

Solute carrier family 26 (anion exchanger), member 4

SMAD:

Homologs of the Drosophila protein, mothers against decapentaplegic (MAD)

Smurf1/2:

SMAD specific E3 ubiquitin protein ligase 1/2

SUMO:

Small Ubiquitin-like MOdifier

UBC9:

UBiquitin-conjugating 9

UCHs:

Ubiquitin C-terminal hydrolases

Usp53:

Ubiquitin-specific protease 53

USPs:

Ubiquitin-specific proteases

Wnt:

Wingless-related integration site

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Acknowledgments

BM is Research Director from the Belgian National Funds for Scientific Research (FNRS). This work was supported by Grants from the FSR-FNRS, the Fonds Léon Fredericq, the Fondation Médicale Reine Elisabeth, and the Belgian Science Policy (IAP-VII network P7/07). We thank Bernard Minguet for his assistance with Fig. 4.

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  1. Developmental Neurobiology Unit, GIGA-Neurosciences, University of Liège, Quartier Hôpital (CHU), Avenue Hippocrate 15, Tour 4, 1er étage, Bât. B36, 4000, Liège, Belgium

    Susana Mateo Sánchez, Stephen D. Freeman, Laurence Delacroix & Brigitte Malgrange

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Mateo Sánchez, S., Freeman, S.D., Delacroix, L. et al. The role of post-translational modifications in hearing and deafness. Cell. Mol. Life Sci. 73, 3521–3533 (2016). https://doi.org/10.1007/s00018-016-2257-3

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