PgmNr Z6140: Involvement of The p62-Nrf2 Pathway as A Protection Mechanism against Spns1 Deficiency in Zebrafish.

Authors:
A. Khan 1 ; S. Lian 1 ; T. Sasaki 1 ; M. Kobayashi 2 ; S. Kishi 1


Institutes
1) The Scripps Research Institute, Jupiter, FL; 2) University of Tsukuba, Japan.


Abstract:

The protein Nrf2 is a transcription factor which regulates the expression of various antioxidant genes in cells. p62/SQSTM1 functions as a cargo receptor for autophagy and also in the non‐canonical activation of Nrf2. Using transgenic zebrafish that express multiple reporters which allow simultaneous monitoring of Nrf2 activation and autophagy, we demonstrate that chemical and genetic inductions of stress and autophagic responses are reciprocally linked to developmental senescence. Deficiency of the lysosomal sympoter Spns1 was exacerbated by loss of either Nrf2 or p53 individually. However, acceleration of senescence due to the loss of Nrf2 in spns1-mutant embryos was partially counteracted by the p53 defect, suggesting that Nrf2 plays a protective role against autolysosomal deterioration induced by Spns1 deficiency through a different mechanism from p53. Intriguingly, a newly identified chemical potentiator of Nrf2 in our system, but not other authentic Nrf2 activators, ameliorates spns1-mutant phenotypes. We further found that chemically and genetically enhanced p62 aggregations are involved in the mechanism of Nrf2-induced protection against Spns1-deficent pathogenesis. Together, these data suggest that chemical genetic boosting of the p62-Nrf2 axis protects against the deteriorative impact induced by Spns1 deficiency, a condition in which autolysosomal clearance is disrupted.



ZFIN Genetics Index
1. spns1
2. nfe2l2a
3. sqstm1
4. tp53