Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

When tissues are injured and blood vessels clotted, the local environment becomes ischemic – lack of adequate supply of oxygen and glucose delivered to the surrounding cells. The heat shock protein-90 (Hsp90) family proteins protect tissues from various environmental insults and participate in the damaged tissue repair. Here we report discovery of a novel ischemia-responsive mechanism by which the two Hsp90 isoforms, Hsp90α and Hsp90β, work together to promote cell motility in wounded skin and accelerate wound closure. We demonstrate that Hsp90α and Hsp90β have distinct and non-exchangeable functions during wound healing. Under hypoxia and lack of serum factors, Hsp90β binds to the cytoplasmic tail of the LDL Receptor-Related Protein-1 (LRP-1) and stabilizes the receptor at the cell surface. Hsp90α, however, is secreted by the cell into extracellular space, where it binds and signals through the LRP-1 receptor to promote cell motility, leading to wound closure. In addition to skin injury, we suggest that this repair mechanism applies broadly to other non-cutaneous injured tissues.