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Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation.

ABSTRACT: Corneal wound healing is essential for the maintenance of corneal integrity and transparency and involves a series of physiological processes that depend on the proliferation of epithelial cells. However, the molecular mechanisms that control corneal epithelial cell proliferation are poorly understood. Here, we show that Sestrin2, a stress-inducible protein, is downregulated in the corneal epithelium during wound healing and that the proliferation of epithelial basal cells is enhanced in Sestrin2-deficient mice. We also show that YAP, a major downstream effector of the Hippo signaling pathway, regulates cell proliferation during corneal epithelial wound repair and that Sestrin2 suppresses its activity. Moreover, increased levels of reactive oxygen species in the Sestrin2-deficient corneal epithelium promote the nuclear localization and dephosphorylation of YAP, activating it to enhance the proliferation of corneal epithelial cells. These results reveal that Sestrin2 is a negative regulator of YAP, which regulates the proliferative capacity of basal epithelial cells, and may serve as a potential therapeutic target for corneal epithelial damage.

SUBMITTER: Lee JS

PROVIDER: S-EPMC7338388 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation.

Lee Ji-Su JS Park Hwan-Woo HW Cho Kyong Jin KJ Lyu Jungmook J

Experimental & molecular medicine 20200612 6

Corneal wound healing is essential for the maintenance of corneal integrity and transparency and involves a series of physiological processes that depend on the proliferation of epithelial cells. However, the molecular mechanisms that control corneal epithelial cell proliferation are poorly understood. Here, we show that Sestrin2, a stress-inducible protein, is downregulated in the corneal epithelium during wound healing and that the proliferation of epithelial basal cells is enhanced in Sestrin ...[more]

PMID: 32528056

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Project description:PurposeDual specificity phosphatases (DUSPs) modulate the duration and magnitude of phospho-activation of Erk1/2, p38 and JNK1/2, the terminal kinases (TKs) of the mitogen activated protein kinase (MAPK) cascades. Three DUSPs, DUSP1, DUSP5, and DUSP6, are overexpressed in ocular surface side population stem cells (SPSCs). Our objective was to identify the impact of these enzymes on TK phosphorylation and proliferation of corneal epithelial cells.MethodsSV40 immortalized (sv) and expanded fresh human corneal epithelial cells (efHCECs) were transduced with lentivectors to elicit expression of shRNAmir against DUSP1, DUSP5, and JNK1 to thereby create the DUSP1i, DUSP5i and JNKi cell sublines, or overexpress DUSP6 (henceforth DUSP6(+)), respectively. TK phosphorylation status and proliferation rates were determined by immunoblotting and (3)H thymidine uptake.ResultsIn both ef and svHCECs, EGF supplementation after a 24 h serum starvation caused a rapid 5-15 min spike in the phosphorylation of all three TK types. This was followed by gradual decreases to low phosphorylation levels within one h. These declines coincided with dramatic increases in DUSP1 and DUSP5 protein expression. In DUSP1i, the DUSP1 increase was abolished. All 3 TKs maintained high phosphorylation levels for at least 90 min and proliferation rates were unchanged from non-transduced cells. In DUSP5i, the DUSP5 protein increase was prevented, the post peak phosphorylation decrease occurred only on Erk1/2 and the proliferation rate increased by 50%-60%. In JNK1i, JNK1 was essentially knocked out and proliferation rates were also markedly elevated. At steady-state, DUSP1i maintained high levels of pJNK1/2 expression. In DUSP6(+) Erk1/2 phosphorylation was prevented and proliferation rates decreased to less than 50%.ConclusionsDUSP5 and DUSP6 selectively control ERK pathway activity and proliferation. The lack of an effect of DUSP1 knockdown on proliferation can be attributed to its pan-MAPK effect. The expected augmented proliferative response due to enhanced and prolonged phosphorylation of Erk1/2 following DUSP1 knockdown does not occur because a pJNK1/2 antiproliferative effect is simultaneously unleashed.

Dataset Information

Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation.

Publications

Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation.

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