Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.
Xinliang LuZhengbo SongJiayue HaoXianghui KongWeiyi YuanYingying ShenChengyan ZhangJie YangPengfei YuYun QianGensheng ZhangHuajun FengJianli WangZhenzhai CaiZhijian CaiPublished in: Journal of extracellular vesicles (2024)
Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.
Keyphrases
- liver failure
- drug delivery
- drug induced
- hepatitis b virus
- cancer therapy
- high glucose
- single cell
- diabetic rats
- induced apoptosis
- small molecule
- stem cells
- protein protein
- dna methylation
- gene expression
- oxidative stress
- emergency department
- risk assessment
- climate change
- nucleic acid
- endoplasmic reticulum stress
- mechanical ventilation