Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate

Thorsten Schaefer¹, Nitish Mittal², Hui Wang³, Meric Ataman², Silvia Candido⁴, Jonas Lötscher⁴, Sergiy Velychko⁵, Lionel Tintignac⁴, Thomas Bock⁶, Anastasiya Börsch⁴, Jochen Baßler⁷, Tata Nageswara Rao⁸, Jakub Zmajkovic⁹, Sarah Roffeis⁴, Jordan Löliger⁴, Francis Jacob⁴, Alain Dumlin⁴, Christoph Schürch⁴, Alexander Schmidt⁶, Radek C Skoda⁴, Matthias P Wymann⁴, Christoph Hess¹⁰, Hans R Schöler¹¹, Holm Zaehres¹², Ed Hurt⁷, Mihaela Zavolan², Claudia Lengerke¹³

Affiliations

¹ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Electronic address: thorsten.schaefer@unibas.ch.
² Biozentrum, University of Basel, Basel, Switzerland.
³ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Shanghai University of Medicine and Health Sciences, Shanghai, China.
⁴ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
⁵ Max Planck Institute for Molecular Biomedicine, Münster, Germany; Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁶ Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
⁷ Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany.
⁸ Medical Research Center, Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Institute of Pharmacology, University of Bern, Bern, Switzerland.
⁹ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Research Institute of Molecular Pathology (IMP), Vienna, Austria.
¹⁰ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; CITIID, Department of Medicine, University of Cambridge, Cambridge, UK.
¹¹ Max Planck Institute for Molecular Biomedicine, Münster, Germany.
¹² Max Planck Institute for Molecular Biomedicine, Münster, Germany; Institute of Anatomy, Ruhr University Bochum, Bochum, Germany.
¹³ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Internal Medicine II, University Hospital Tübingen, Tübingen, Germany.

PMID: 39368083
DOI: 10.1016/j.celrep.2024.114807

Free article

Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate

Thorsten Schaefer et al. Cell Rep. 2024.

Free article

. 2024 Oct 22;43(10):114807.

doi: 10.1016/j.celrep.2024.114807. Epub 2024 Oct 3.

Authors

Affiliations

¹ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Electronic address: thorsten.schaefer@unibas.ch.
² Biozentrum, University of Basel, Basel, Switzerland.
³ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Shanghai University of Medicine and Health Sciences, Shanghai, China.
⁴ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
⁵ Max Planck Institute for Molecular Biomedicine, Münster, Germany; Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁶ Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
⁷ Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany.
⁸ Medical Research Center, Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Institute of Pharmacology, University of Bern, Bern, Switzerland.
⁹ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Research Institute of Molecular Pathology (IMP), Vienna, Austria.
¹⁰ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; CITIID, Department of Medicine, University of Cambridge, Cambridge, UK.
¹¹ Max Planck Institute for Molecular Biomedicine, Münster, Germany.
¹² Max Planck Institute for Molecular Biomedicine, Münster, Germany; Institute of Anatomy, Ruhr University Bochum, Bochum, Germany.
¹³ Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Internal Medicine II, University Hospital Tübingen, Tübingen, Germany.

PMID: 39368083
DOI: 10.1016/j.celrep.2024.114807

Abstract

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.

Keywords: CP: Developmental biology; CP: Molecular biology; SOX2; cancer; differentiation; ribosome; stem cell; translation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate

Affiliations

Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate

Authors

Affiliations

Abstract

Conflict of interest statement

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Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous