Stress inducible phosphoprotein 1 (STIP1) is a critical stemness regulator in mouse embryonic stem cells and early mammalian development

Stress-inducible phosphoprotein 1 (STIP1/STI1/HOP) is a co-chaperone that plays a pivotal role in proteostasis. Knockout of STIP1 leads to early embryonic lethality in mice, but its precise function in embryogenesis remains unknown. Thus, we mined single-cell RNA sequencing data from mouse embryos, finding that Stip1 is co-expressed with the core pluripotency transcription factors, highlighting a potential function of this protein in regulating stemness. This was confirmed by the derivation of mouse embryonic stem cell (mESC) lines from genetically-modified Stip1 mice. mESCs with decreased STIP1 levels presented low expression of essential pluripotency markers, impaired proliferation, and increased apoptosis and DNA damage. Conversely, mESCs overexpressing STIP1 showed elevated expression of stemness markers, enhanced proliferation, and reduced DNA damage and apoptosis. Finally, we reveal that cell cycle progression and DNA damage response proteins are altered in mESCs with differential STIP1 levels. Our work sheds light on the function of (antes era "on a novel function of") the co-chaperone STIP1 as a pivotal regulator of the pluripotent phenotype and embryogenesis.