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Gain-of-function variants in GSDME cause pyroptosis and apoptosis associated with post-lingual hearing loss.
Xiao, Yun; Chen, Lei; Xu, Kaifan; Zhou, Meijuan; Han, Yuechen; Luo, Jianfen; Ai, Yu; Wang, Mingming; Jin, Yu; Qiao, Ruifeng; Kong, Shuhui; Fan, Zhaomin; Xu, Lei; Wang, Haibo.
Afiliación
  • Xiao Y; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Chen L; Shandong Institute of Otorhinolaryngology, Jinan, Shandong, China.
  • Xu K; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Zhou M; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Han Y; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Luo J; Shandong Institute of Otorhinolaryngology, Jinan, Shandong, China.
  • Ai Y; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Wang M; Hearing and Balance Biomedical Engineering Laboratory, Shandong Provincial ENT Hospital, Jinan, Shandong, China.
  • Jin Y; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Qiao R; Auditory Implant Center, Shandong Provincial ENT Hospital, Jinan, Shandong, China.
  • Kong S; Hearing and Balance Biomedical Engineering Laboratory, Shandong Provincial ENT Hospital, Jinan, Shandong, China.
  • Fan Z; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, Shandong, China.
  • Xu L; Clinical Audiology Center, Shandong Provincial ENT Hospital, Jinan, Shandong, China.
  • Wang H; Hearing and Balance Biomedical Engineering Laboratory, Shandong Provincial ENT Hospital, Jinan, Shandong, China.
Hum Genet ; 143(8): 979-993, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39066985
ABSTRACT
Gasdermin E (GSDME), a member of the gasdermin protein family, is associated with post-lingual hearing loss. All GSDME pathogenic mutations lead to skipping exon 8; however, the molecular mechanisms underlying hearing loss caused by GSDME mutants remain unclear. GSDME was recently identified as one of the mediators of programmed cell death, including apoptosis and pyroptosis. Therefore, in this study, we injected mice with GSDME mutant (MT) and examined the expression levels to assess its effect on hearing impairment. We observed loss of hair cells in the organ of Corti and spiral ganglion neurons. Further, the N-terminal release from the GSDME mutant in HEI-OC1 cells caused pyroptosis, characterized by cell swelling and rupture of the plasma membrane, releasing lactate dehydrogenase and cytokines such as interleukin-1ß. We also observed that the N-terminal release from GSDME mutants could permeabilize the mitochondrial membrane, releasing cytochromes and activating the mitochondrial apoptotic pathway, thereby generating possible positive feedback on the cleavage of GSDME. Furthermore, we found that treatment with disulfiram or dimethyl fumarate might inhibit pyroptosis and apoptosis by inhibiting the release of GSDME-N from GSDME mutants. In conclusion, this study elucidated the molecular mechanism associated with hearing loss caused by GSDME gene mutations, offering novel insights for potential treatment strategies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Piroptosis Límite: Animals / Humans Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Piroptosis Límite: Animals / Humans Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania