Cell Reports (Oct 2024)
Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate
- Thorsten Schaefer,
- Nitish Mittal,
- Hui Wang,
- Meric Ataman,
- Silvia Candido,
- Jonas Lötscher,
- Sergiy Velychko,
- Lionel Tintignac,
- Thomas Bock,
- Anastasiya Börsch,
- Jochen Baßler,
- Tata Nageswara Rao,
- Jakub Zmajkovic,
- Sarah Roffeis,
- Jordan Löliger,
- Francis Jacob,
- Alain Dumlin,
- Christoph Schürch,
- Alexander Schmidt,
- Radek C. Skoda,
- Matthias P. Wymann,
- Christoph Hess,
- Hans R. Schöler,
- Holm Zaehres,
- Ed Hurt,
- Mihaela Zavolan,
- Claudia Lengerke
Affiliations
- Thorsten Schaefer
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Corresponding author
- Nitish Mittal
- Biozentrum, University of Basel, Basel, Switzerland
- Hui Wang
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Shanghai University of Medicine and Health Sciences, Shanghai, China
- Meric Ataman
- Biozentrum, University of Basel, Basel, Switzerland
- Silvia Candido
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Jonas Lötscher
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Sergiy Velychko
- Max Planck Institute for Molecular Biomedicine, Münster, Germany; Department of Genetics, Harvard Medical School, Boston, MA, USA
- Lionel Tintignac
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Thomas Bock
- Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland
- Anastasiya Börsch
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Jochen Baßler
- Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany
- Tata Nageswara Rao
- Medical Research Center, Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Institute of Pharmacology, University of Bern, Bern, Switzerland
- Jakub Zmajkovic
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Research Institute of Molecular Pathology (IMP), Vienna, Austria
- Sarah Roffeis
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Jordan Löliger
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Francis Jacob
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Alain Dumlin
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Christoph Schürch
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Alexander Schmidt
- Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland
- Radek C. Skoda
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Matthias P. Wymann
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- Christoph Hess
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; CITIID, Department of Medicine, University of Cambridge, Cambridge, UK
- Hans R. Schöler
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
- Holm Zaehres
- Max Planck Institute for Molecular Biomedicine, Münster, Germany; Institute of Anatomy, Ruhr University Bochum, Bochum, Germany
- Ed Hurt
- Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany
- Mihaela Zavolan
- Biozentrum, University of Basel, Basel, Switzerland
- Claudia Lengerke
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
- Journal volume & issue
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Vol. 43,
no. 10
p. 114807
Abstract
Summary: Stemness and pluripotency are mediated by transcriptional master regulators that promote self-renewal and repress cell differentiation, among which is the high-mobility group (HMG) box transcription factor SOX2. Dysregulated SOX2 expression, by contrast, leads to transcriptional aberrations relevant to oncogenic transformation, cancer progression, metastasis, therapy resistance, and relapse. Here, we report a post-transcriptional mechanism by which the cytosolic pool of SOX2 contributes to these events in an unsuspected manner. Specifically, a low-complexity region within SOX2’s C-terminal segment connects to the ribosome to modulate the expression of cognate downstream factors. Independent of nuclear structures or DNA, this C-terminal functionality alone changes metabolic properties and induces non-adhesive growth when expressed in the cytosol of SOX2 knockout cells. We thus propose a revised model of SOX2 action where nuclear and cytosolic fractions cooperate to impose cell fate decisions via both transcriptional and translational mechanisms.
