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

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.