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

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.