Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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 September 6, 2018
Citation Information: J Clin Invest. 2018;128(11):5150-5162. https://doi.org/10.1172/JCI97498.
View: Text | PDF
Research Article Cell biology Otology Article has an altmetric score of 37

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

  • Text
  • PDF
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

×

Figure 7

Upregulation of the UPR in Tmtc4-KO cells and cochleae.

Options: View larger image (or click on image) Download as PowerPoint
Upregulation of the UPR in Tmtc4-KO cells and cochleae.
(A) mRNA levels ...
(A) mRNA levels of 3 genes (Chop, S-XBP1, and BiP) that represent the 3 principal arms of the UPR were measured in fibroblasts treated with the SERCA2B inhibitor thapsigargin (TG). Treatment of fibroblasts from WT and Tmtc4-KO mice with TG elicited an exaggerated upregulation of all 3 UPR effectors in KO compared with WT cells, as measured relative to expression of GAPDH and to unexposed KO and WT fibroblasts, respectively, by the 2ΔΔct method. (B) FACS sorting of KO and WT cells positive for staining with antibody against Chop shows a greater percentage of KO cells (29.9% vs 0.5% of WT cells) positive for Chop expression. P2: gating set at 3 SD from the mean fluorescence for WT cells. (C) mRNA levels of Chop, S-XBP1, and BiP were also upregulated to a greater extent in Tmtc4-KO cochlear explant cultures treated with TG compared with WT control cultures. TG treatment also induced apoptosis in KO cochlear cultures, as measured by the expression of caspase 3. Data represent the mean and SD of 3 independent experiments; culture dishes of confluent fibroblasts (A) or single cochlear cultures (C). *P < 0.01; **P < 0.001 by 1-way ANOVA followed by Tukey’s multiple comparisons test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 3 news outlets
Blogged by 1
Posted by 5 X users
Referenced in 5 patents
36 readers on Mendeley
See more details