Caveolin 1 Inhibits Keratinocyte Migration And Wound Closure By Orchestrating Cytoskeletal Reorganization
Ivan Jozic1, Andrew P. Sawaya1, George D. Glinos1, Lulu L. Wong1, Tongyu C. Wikramanayake1, Irena Pastar1, Robert S. Kisner1, Harold Brem2, Marjana Tomic-Canic1
1University of Miami Miller School of Medicine, Miami, FL, USA, 2Winthrop Hospital/Stony Brook University, Stony Brook, NY, USA
By oligomerization at caveolae, caveolins (cavs) can compartmentalize various signal transduction molecules, affording orchestration of transmembrane signaling events and allowing cross-talk between various downstream effectors, either sequestering certain proteins from their normal function(s) or bringing other molecules in close proximity to interact with each other. Previously, we have shown that membrane-bound glucocorticoid receptor (mbGR) mediates inhibition of keratinocyte migration during wound healing. To further understand the mechanism of this inhibition, we tested downstream targets of glucocorticoids (GC) signaling. We found that GCs upregulate cav1 expression and downregulate Rho GTPase Activating Protein 35 (ArhGAP35) expression in human keratinocytes in vitro and human wounds ex vivo. This results in increased stress fiber formation that leads to inhibition of keratinocyte migration. Furthermore, we show that upon GC treatment, cav1 co-localizes with both GR and EGFR. By disrupting caveolae, either through MβCD-mediated depletion of membrane cholesterol or CRISPR/Cas9-mediated knockdown, we detect a reversal of GR-mediated inhibition of keratinocyte migration, and a rescue of EGFR from cav1 sequestration within the caveolae, all of which improved wound healing outcomes. Interestingly, we observed that cav1 is spatiotemporally downregulated during acute wound healing and is strikingly absent from migrating epithelium, thus confirming its healing-inhibitory role. Moreover, cav1 is significantly upregulated in patients with non-healing chronic wounds, further underscoring its inhibitory role. Together our data provide evidence for a novel molecular mechanism by which cav1 inhibits keratinocyte migration and wound re-epithelialization and offers multiple novel therapeutic avenues.
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