Interplay between Nrf2 and & alpha;B-crystallin in the lens and heart of zebrafish under proteostatic stress

A coordinated oxidative stress response, partly triggered by the transcription factor Nrf2, protects cells from the continual production of reactive oxygen species. Left unbuffered, reactive oxygen species can lead to protein aggregation that has been implicated in a spectrum of diseases such as cataract of the ocular lens and myopathy of the heart. While proteostasis is maintained by diverse families of heat shock proteins, the interplay between the oxidative and proteostatic stress responses in the lens and heart has not been investigated. Capitalizing on multiple zebrafish lines that have compromised function of Nrf2 and/or the two zebrafish small heat shock proteins aBa- and aBb-crystallin, we uncovered a transcriptional relationship that leads to a substantial increase in aBb-crystallin transcripts in the heart in response to compromised function of Nrf2. In the lens, the concomitant loss of function of Nrf2 and aBa-crystallin leads to upregulation of the cholesterol biosynthesis pathway, thus mitigating the phenotypic consequences of the aBa-crystallin knockout. By contrast, abrogation of Nrf2 function accentuates the penetrance of a heart edema phenotype characteristic of embryos of aB-crystallin knockout lines. Multiple molecular pathways, such as genes involved in extracellular interactions and implicated in cardiomyopathy, are revealed from transcriptome profiling, thus identifying novel targets for further investigation. Together, our transcriptome/phenotypic analysis establishes an intersection between oxidative stress and chaperone responses in the lens and heart.

Automated summary

A coordinated oxidative stress response, partly triggered by the transcription factor Nrf2, protects cells from harmful reactive oxygen species. The interplay between oxidative stress and chaperone responses in the lens and heart remains unexplored.