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

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: jason.moffat@sickkids.ca.

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

Free article

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

Yu-Xi Xiao et al. Cell Rep. 2024.

Free article

. 2024 Jul 23;43(7):114417.

doi: 10.1016/j.celrep.2024.114417. Epub 2024 Jul 8.

Authors

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: jason.moffat@sickkids.ca.

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources