Hsp90α and Hsp90β together operate a hypoxia and nutrient paucity stress-response mechanism during wound healing.
When tissues are injured and blood vessels clot, the local environment becomes ischemic, meaning that there is a 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 repair of damaged tissue. Here, we report discovery of a new ischemia-responsive mechanism in which the two Hsp90 isoforms Hsp90α and Hsp90β (also known as HSP90AA1 and HSP90AB1, respectively) 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 when there is a 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.
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Priyamvada
P
Jayaprakash
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Hangming
H
Dong
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Mengchen
M
Zou
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Ayesha
A
Bhatia
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Kathryn
K
O'Brien
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Mei
M
Chen
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
David T
DT
Woodley
Department of Dermatology and the Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA wli@usc.edu.
Wei
W
Li
D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D012867:Skin / Q000166:cytology; D013552:Swine; D014945:Wound Healing / Q000502:physiology*
D018841:HSP90 Heat-Shock Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020033:Protein Isoforms
Cell motility; Extracellular Hsp90; Hypoxia; Wound healing