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Biochem Biophys Res Commun. 2019 Jun 6. pii: S0006-291X(19)31075-7. doi: 10.1016/j.bbrc.2019.05.171. [Epub ahead of print]

Targeting cullin 3 by miR-601 activates Nrf2 signaling to protect retinal pigment epithelium cells from hydrogen peroxide.

Author information

1
The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; Department of Ophthalmology, Children's Hospital of Nanjing Medical University, Nanjing, China.
2
The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
3
The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China. Electronic address: Jqin710@vip.sina.com.

Abstract

Activation of Nrf2 cascade can protect retinal pigment epithelium (RPE) cells from hydrogen peroxide (H2O2) and other oxidative injury. The current study identified microRNA-601 (miR-601) as a novel cullin 3 (Cul3)-targeting miRNA that activates Nrf2 cascade. In ARPE-19 cells and primary human RPE cells, forced overexpression of miR-601 significantly inhibited Cul3 3'-UTR activity and downregulated Cul3 mRNA/protein expression, leading to Nrf2 protein stabilization and its nuclear translocation as well as expression of anti-oxidant response elements (ARE)-dependent genes (HO1, NQO1 and GCLC). H2O2 treatment increased miR-601 levels in RPE cells. Significantly, ectopic miR-601 overexpression attenuated H2O2-induced oxidative injury and apoptosis in RPE cells. In contrast, miR-601 inhibition promoted Cul3 expression, lowered basal Nrf2 activation, and enhanced H2O2-induced oxidative stress and apoptosis in RPE cells. In ARPE-19 cells, CRISPC/Cas9-mediated knockout (KO) of Cul3 or Keap1 not only mimicked, but also nullified, miR-601-inudced anti-H2O2 actions. Furthermore, Nrf2 silencing by targeted shRNAs abolished miR-601-inudced cytoprotection in H2O2-treated ARPE-19 cells. Taken together, we show that miR-601 activates Nrf2 signaling to protect RPE cells from H2O2 by targeting Cul3.

KEYWORDS:

Nrf2; Oxidative injury; Retinal pigment epithelium cells; cullin 3; miR-601

PMID:
31178131
DOI:
10.1016/j.bbrc.2019.05.171

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