Critical role of WNK1 in MYC-dependent early thymocyte development

Köchl, R.; Vanes, L.; Llorian Sopena, M.; Chakravarty, P.; Hartweger, H.; Fountain, K.; White, A.; Cowan, J.; Anderson, G.; Tybulewicz, V.

doi:10.1101/2020.06.11.147017

bioRxiv · 10.1101/2020.06.11.147017

Critical role of WNK1 in MYC-dependent early thymocyte development

Köchl, R.·Vanes, L.·Llorian Sopena, M.·Chakravarty, P.·Hartweger, H.·Fountain, K.·White, A.·Cowan, J.·Anderson, G.·Tybulewicz, V.

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Abstract

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the {beta}-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

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Köchl, R., Vanes, L., Llorian Sopena, M., Chakravarty, P., Hartweger, H., Fountain, K., White, A., Cowan, J., Anderson, G., Tybulewicz, V.. 2020-06-12. Critical role of WNK1 in MYC-dependent early thymocyte development. https://doi.org/10.1101/2020.06.11.147017

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