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Concomitant ablation of SOS1 and SOS2 triggers a lethal phenotype involving compromised intestinal integrity and widespread septicemia

Nature作者：Andrea Olarte-San Juan2026年8月12日正文已收录本站
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  • Open access
  • Published:
  • Pablo Rodríguez-Ramos  ORCID: orcid.org/0000-0002-3766-14061,
  • Alba Díaz-Aguilera1,
  • Nuria Calzada1,
  • Carmela Gómez  ORCID: orcid.org/0000-0002-9041-886X1,2,
  • Rocío Fuentes-Mateos3,4,
  • Alberto Fernández-Medarde  ORCID: orcid.org/0000-0002-1230-55011,
  • Rubén Nogueiras  ORCID: orcid.org/0000-0002-9976-99305,
  • David Díaz6,7,
  • Eugenio Santos  ORCID: orcid.org/0000-0003-3565-03211 &
  • …
  • Rósula García-Navas  ORCID: orcid.org/0000-0002-8956-39041,8 

Cell Death & Disease (2026) Cite this article

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Abstract

The RAS guanine nucleotide exchange factors Son of Sevenless 1 and 2 (SOS1 and SOS2) are key regulators of RAS signaling pathways controlling cellular proliferation, differentiation, and survival processes that are essential for correct tissue homeostasis. While mice lacking both SOS1 and SOS2 die precipitously, we demonstrate herein that the combined genetic ablation of SOS1 and SOS2 triggers spontaneous, gut-derived, lethal bacteremia. Double-knockout (DKO) SOS1/2 mice exhibit extensive intestinal tissue damage, massive bacterial leakage out of the gut, and rapid progression to multi-organ failure and death. At the cellular level, loss of both SOS1 and SOS2 leads to profound immune cell depletion and a marked reduction in intestinal stem cell abundance and proliferative capacity, which is accompanied by severe disruption of intestinal architecture and increased epithelial permeability, indicating a breakdown of gut barrier integrity. Notably, therapeutic interventions aimed at enhancing cellular stemness significantly improve survival in SOS1/2 DKO mice, restoring intestinal proliferation and tissue organization. Collectively, our findings identify SOS1 and SOS2 as critical regulators of intestinal homeostasis and regenerative capacity during systemic infection and reveal stemness reinforcement as a potential strategy to overcome lethal susceptibility to sepsis.

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Acknowledgements

The authors wish to thank the Pathology Unit, the Mouse Model Experimentation Unit, and the Advanced Cellular Analysis Unit at CIC for their assistance in carrying out this work.

Funding

Work supported by grants from ISCIII-MCUI (FISPI22/01538 & PI25/01247); JCyL (SA264P18 & SA222P23 to UIC 076); ISCIII-CIBERONC (group CB16/12/00352); and Fundación Solorzano-Barruso (FS/7-2022). Research co-financed by FEDER funds and supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of Castilla y León (CLC-2017- 01) and AECC Excellence program Stop Ras Cancer (EPAEC222641CICS).

Author information

Authors and Affiliations

  1. Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, CIBERONC, Salamanca, Spain

    Andrea Olarte-San Juan, Pablo Rodríguez-Ramos, Alba Díaz-Aguilera, Nuria Calzada, Carmela Gómez, Alberto Fernández-Medarde, Eugenio Santos & Rósula García-Navas

  2. Departamento de Anatomía e Histología Humana, Facultad de Medicina, Universidad de Salamanca. Campus Miguel de Unamuno, Salamanca, Spain

    Carmela Gómez

  3. Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands

    Rocío Fuentes-Mateos

  4. Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Rocío Fuentes-Mateos

  5. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain; Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain

    Rubén Nogueiras

  6. Laboratory of Neuronal Plasticity and Neurorepair, Institute for Neuroscience of Castile and León (INCyL), Universidad de Salamanca, Salamanca, Spain

    David Díaz

  7. Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain

    David Díaz

  8. Universidad Internacional de Valencia, Valencia, Spain

    Rósula García-Navas

Authors

  1. Andrea Olarte-San Juan
  2. Pablo Rodríguez-Ramos
  3. Alba Díaz-Aguilera
  4. Nuria Calzada
  5. Carmela Gómez
  6. Rocío Fuentes-Mateos
  7. Alberto Fernández-Medarde
  8. Rubén Nogueiras
  9. David Díaz
  10. Eugenio Santos
  11. Rósula García-Navas

Corresponding authors

Correspondence to Eugenio Santos or Rósula García-Navas.

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Competing interests

The authors declare no competing interests.

Ethical approval

All mouse experiments were approved by the Bioethics Committee of the University of Salamanca (#987, #1263) and conducted at its NUCLEUS animal facility in accordance with European (2007/526/CE) and Spanish (RD53/2013) guidelines for animal care and experimentation.

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Edited by Dr Cristina Munoz-Pinedo

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Olarte-San Juan, A., Rodríguez-Ramos, P., Díaz-Aguilera, A. et al. Concomitant ablation of SOS1 and SOS2 triggers a lethal phenotype involving compromised intestinal integrity and widespread septicemia. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-09185-z

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  • DOI: https://doi.org/10.1038/s41419-026-09185-z