The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation

Yu-Xi Xiao; Seon Yong Lee; Magali Aguilera-Uribe; Reuben Samson; Aaron Au; Yukti Khanna; Zetao Liu; Ran Cheng; Kamaldeep Aulakh; Jiarun Wei; Adrian Granda Farias; Taylor Reilly; Saba Birkadze; Andrea Habsid; Kevin R Brown; Katherine Chan; Patricia Mero; Jie Qi Huang; Maximilian Billmann; Mahfuzur Rahman; Chad Myers; Brenda J Andrews; Ji-Young Youn; Christopher M Yip; Daniela Rotin; W Brent Derry; Julie D Forman-Kay; Alan M Moses; Iva Pritišanac; Anne-Claude Gingras; Jason Moffat

doi:10.1016/j.celrep.2024.114417

The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation

Cell Rep. 2024 Jul 23;43(7):114417. doi: 10.1016/j.celrep.2024.114417. Epub 2024 Jul 8.

Authors

Yu-Xi Xiao¹, Seon Yong Lee², Magali Aguilera-Uribe¹, Reuben Samson³, Aaron Au⁴, Yukti Khanna⁵, Zetao Liu⁶, Ran Cheng⁷, Kamaldeep Aulakh², Jiarun Wei², Adrian Granda Farias¹, Taylor Reilly¹, Saba Birkadze¹, Andrea Habsid², Kevin R Brown², Katherine Chan², Patricia Mero², Jie Qi Huang⁸, Maximilian Billmann⁹, Mahfuzur Rahman¹⁰, Chad Myers¹⁰, Brenda J Andrews¹¹, Ji-Young Youn⁸, Christopher M Yip¹², Daniela Rotin⁶, W Brent Derry⁷, Julie D Forman-Kay¹³, Alan M Moses¹⁴, Iva Pritišanac⁵, Anne-Claude Gingras³, Jason Moffat¹⁵

Affiliations

¹ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada.
⁴ Institute for Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada; Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁵ Otto-Loewi Research Center, Division of Medicinal Chemistry, Medical University of Graz, Neue Stiftingtalstrabe 6, 8010, Graz, Austria.
⁶ Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Institute of Human Genetics, School of Medicine and University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
¹⁰ Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Donnelly Centre, University of Toronto, Toronto, ON, Canada.
¹² Institute for Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Donnelly Centre, University of Toronto, Toronto, ON, Canada.
¹³ Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁴ Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.
¹⁵ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Institute for Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected].

PMID: 38980795
DOI: 10.1016/j.celrep.2024.114417

Abstract

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.

Keywords: CP: Molecular biology; NRBP pseudo-kinases; TSC22D family; WNK kinases; biomolecular condensates; cell volume control; essential genes; genetic buffering; genetic interactions; intrinsic disordered regions; paralog dominance.

MeSH terms

Animals
Cell Size*
Evolution, Molecular
HEK293 Cells
Humans
Multigene Family
Osmotic Pressure
Protein Binding
WNK Lysine-Deficient Protein Kinase 1* / genetics
WNK Lysine-Deficient Protein Kinase 1* / metabolism

Substances

WNK Lysine-Deficient Protein Kinase 1
WNK1 protein, human