Critical role of WNK1 in MYC-dependent early mouse thymocyte development

Elife. 2020 Oct 14;9:e56934. doi: 10.7554/eLife.56934.

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 mouse thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the β-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.

Keywords: CXCR4; MYC; WNK1; immunology; inflammation; mouse; pre-TCR; signal transduction; thymocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Mice
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Thymocytes / metabolism*
  • Thymus Gland / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1 / genetics*
  • WNK Lysine-Deficient Protein Kinase 1 / metabolism

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse

Associated data

  • GEO/GSE136210
  • GEO/GSE48138