Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss
Jiang Li, … , Dylan K. Chan, Elliott H. Sherr
Jiang Li, … , Dylan K. Chan, Elliott H. Sherr
Published November 1, 2018; First published September 6, 2018
Citation Information: J Clin Invest. 2018;128(11):5150-5162. https://doi.org/10.1172/JCI97498.
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Categories: Research Article Cell biology Otology

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

Abstract

Hearing loss is a significant public health concern, affecting over 250 million people worldwide. Both genetic and environmental etiologies are linked to hearing loss, but in many cases the underlying cellular pathophysiology is not well understood, highlighting the importance of further discovery. We found that inactivation of the gene Tmtc4 (transmembrane and tetratricopeptide repeat 4), which was broadly expressed in the mouse cochlea, caused acquired hearing loss in mice. Our data showed Tmtc4 enriched in the endoplasmic reticulum, and that it functioned by regulating Ca2+ dynamics and the unfolded protein response (UPR). Given this genetic linkage of the UPR to hearing loss, we demonstrated a direct link between the more common noise-induced hearing loss (NIHL) and the UPR. These experiments suggested a novel approach to treatment. We demonstrated that the small-molecule UPR and stress response modulator ISRIB (integrated stress response inhibitor), which activates eIF2B, prevented NIHL in a mouse model. Moreover, in an inverse genetic complementation approach, we demonstrated that mice with homozygous inactivation of both Tmtc4 and Chop had less hearing loss than knockout of Tmtc4 alone. This study implicated a novel mechanism for hearing impairment, highlighting a potential treatment approach for a broad range of human hearing loss disorders.

Authors

Jiang Li, Omar Akil, Stephanie L. Rouse, Conor W. McLaughlin, Ian R. Matthews, Lawrence R. Lustig, Dylan K. Chan, Elliott H. Sherr

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Figure 9

Inverse complementation assay.

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Inverse complementation assay. (A) As demonstrated in Figure 8, noise ex...
(A) As demonstrated in Figure 8, noise exposure induces expression of the proapoptotic UPR modulator Chop, and pharmacologic inhibition of Chop expression with ISRIB via ATF4 attenuates NIHL. (B) In the genetic model of Tmtc4 deficiency, Tmtc4-KO cochlea demonstrate upregulation of Chop. In an inverse complementation model, we generated double KO mice with both Tmtc4 and Chop deficiency and hypothesized that prevention of Chop expression would attenuate progressive postnatal hearing loss. (C) ABR thresholds were measured for mice of the indicated genotypes for Tmtc4 and Chop. Tmtc4–/– mice were all tested at P19; Tmtc4+/+ mice were all tested at P39 to ensure no long-term hearing loss associated with Chop deficiency alone. Tmtc4–/– mice showed elevated ABR thresholds compared with all Tmtc4+/+ mice; among the Tmtc4–/– mice, Chop–/– genotype was associated with improved hearing compared with Chop+/+ mice. *P < 0.01 by unpaired 2-tailed t test. Data represent mean and SD.