CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis

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.

The zebrafish eye—a paradigm for investigating human ocular genetics

“…Morpholino-induced knockdown of the zebrafish cerkl resulted in increased retinal cell death with rod and cone photoreceptor degeneration. 80 In addition, mutations in c2orf71, the zebrafish orthologue of C2ORF71 (responsible for human RP54), resulted in shortened photoreceptor outer segments, and attenuated visual response to light exposure. 81 The ability to simulate discrete phenotypes associated with human RP in zebrafish models such as these, has proved invaluable in confirming human genes as causative for RP.…”

pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

“…3.2 Hypoxia regulates CERKL abundance at protein level CERKL acts as an antioxidant protein to maintain photoreceptor survival [14,15,17]. Thus, we hypothesize stress condition may up-regulate CERKL as it happens to A C C E P T E D M A N U S C R I P T…”

“…Although CERKL is homologous to ceramide kinase (CERK), it does not phosphorylate ceramide [13]. CERKL is a multifunctional protein, its overexpression protects cells from H 2 O 2 induced apoptosis [14,15], whereas its knockdown sensitizes cells to such insult. CERKL interacts with the mitochondrial thioredoxin (TRX2) antioxidant protein and activates it [15].…”

“…CERKL is a multifunctional protein, its overexpression protects cells from H 2 O 2 induced apoptosis [14,15], whereas its knockdown sensitizes cells to such insult. CERKL interacts with the mitochondrial thioredoxin (TRX2) antioxidant protein and activates it [15]. Additionally, CERKL is an mRNA binding protein and localizes in a cytoplasmic RNA-protein complex called stress granules (SGs), which increases in response to stress conditions [16].…”

“…Additionally, CERKL is an mRNA binding protein and localizes in a cytoplasmic RNA-protein complex called stress granules (SGs), which increases in response to stress conditions [16]. CERKL is critical to photoreceptor survival but not development [17], its deficiency leads to retinal degeneration as a result of oxidative damage in both human [11,18] and animal models [15,17,19]. Although it is pivotal for photoreceptor survival, the regulatory mechanism of CERKL in response to stress remains unclear.…”