Deficiency of HSF4 Increases the Secretion of Small Extracellular Vesicles via Upregulation of Chaperone-Mediated Autophagy

Abstract

Small extracellular vesicles (SEVs) are membrane-bound vesicles secreted by cells that facilitate intercellular communication. This study reveals how heat shock transcription factor 4 (HSF4) deficiency regulates SEV secretion in lens epithelial cells through chaperone-mediated autophagy (CMA). Compared to mLEC/HA-Hsf4b cells, SEVs secreted by HSF4-deficient mLEC/Hsf4^−/− cells showed significantly increased levels of CMA-related proteins (HSP70, HSC70, LAMP2A, and HSP90) and EGFR, while LC3 II levels were reduced. Additionally, EGFR-enriched SEVs activated downstream ERK/AKT signaling pathways, promoting the proliferation and migration of lens epithelial cells and inducing epithelial–mesenchymal transition (EMT). Further inhibition experiments showed that blocking HSP70 and HSP90 with apoptozole and retaspimycin, or silencing LAMP2A with siRNA, reduced SEV secretion in HSF4-deficient cells. Collectively, enhanced CMA activity and increased SEV secretion induced by HSF4 deficiency may represent a potential mechanism underlying congenital cataract development.