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CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis
Chang Li1, Lei Wang1, Jing Zhang2
1Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Abstract:
Mutations in the ceramide kinase-like gene (CERKL) are associated with severe retinal degeneration. However, the exact function of the encoded protein (CERKL) remains unknown. Here we show that CERKL interacts with mitochondrial thioredoxin 2 (TRX2) and maintains TRX2 in the reduced redox state. Overexpression of CERKL protects cells from apoptosis under oxidative stress, whereas suppressing CERKL renders cells more sensitive to oxidative stress. In zebrafish, CERKL protein prominently locates in the outer segment and inner segment of the photoreceptor of the retina. Knockdown of CERKL in the zebrafish leads to an increase of retinal cell death, including cone and rod photoreceptor degeneration. Signs of oxidative damage to macromolecules were also detected in CERKL deficient zebrafish retina. Our results show that CERKL interacts with TRX2 and plays a novel key role in the regulation of the TRX2 antioxidant pathway and, for the first time, provides an explanation of how mutations in CERKL may lead to retinal cell death.
Insights
Mutations in ceramide kinase-like gene (CERKL) cause retinal degeneration by impairing the antioxidant thioredoxin 2 (TRX2) pathway. This study reveals CERKL
Area of Science:
- Molecular Biology
- Cell Biology
- Ophthalmology
Background:
- Mutations in the ceramide kinase-like gene (CERKL) are linked to severe retinal degeneration.
- The precise function of the CERKL protein in retinal health is currently unknown.
Purpose of the Study:
- To elucidate the molecular function of CERKL and its role in retinal degeneration.
- To investigate the interaction of CERKL with other cellular components involved in oxidative stress response.
Main Methods:
- Co-immunoprecipitation assays to identify CERKL interacting partners.
- Cellular assays to assess apoptosis and oxidative stress sensitivity.
- Zebrafish models to study CERKL function in vivo through gene knockdown.
Main Results:
- CERKL directly interacts with mitochondrial thioredoxin 2 (TRX2), maintaining its reduced state.
- Overexpression of CERKL confers protection against oxidative stress-induced apoptosis.
- CERKL knockdown in zebrafish results in photoreceptor degeneration and increased oxidative damage.
Conclusions:
- CERKL plays a critical role in the TRX2 antioxidant pathway, protecting retinal cells from oxidative damage.
- This study provides a mechanistic explanation for how CERKL mutations lead to retinal cell death and degeneration.
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