A hypomorphic Stip1 allele reveals the requirement for chaperone networks in mouse development and aging

The chaperone machinery is well conserved from yeast to mammals, however our knowledge of their impact on mammalian physiology is lagging. Stress-inducible phosphoprotein-1 (STI1; STIP1; Hop) is a co-chaperone that simultaneously interacts with Hsp70 and Hsp90 via three tetratricopeptide repeat (TPR) domains, of which TPR1 and TPR2B may be redundant in yeast. In-depth analysis of human datasets indicated that STI1 belongs to a set of co-chaperones that is essential in humans and that the TPR1 domain is evolutionarily conserved, suggesting that in mammals it may be required for optimal STI1 activity in vivo. We generated mice with a hypomorphic Stip1 allele lacking the TPR1 domain. While these mice are viable, they presented decreased levels of Hsp90 client proteins and co-chaperones, suggesting profound dysregulation of chaperone networks. We used this hypomorphic STI1 mutant mouse line to investigate the requirement of STI1-mediated regulation of chaperone networks in mouse physiology. Embryonic cell pluripotency was severely affected by decreased STI1 activity, contributing to the abnormal development in these mice. Moreover, adult TPR1-deprived STI1 mice presented age-related hippocampal neurodegeneration, resulting in compromised memory recall. Our findings reveal a requirement for optimal regulation of chaperone networks and their clients during development and strict dependence on full STI1 activity for healthy neuronal aging. These experiments demonstrate the unique experimental power of using hypomorphic alleles to reveal how chaperone networks regulate mammalian physiology.