Endothelial surface translocation of mitochondrial PDCE2 involves the non-canonical secretory autophagy pathway: Putative molecular target for radiation-guided drug delivery

• Published in: Experimental cell research 2021-08, Vol.405 (2), p.112688-112688, Article 112688
• Main Authors: Faqihi, F., Stoodley, M.A., McRobb, L.S.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Autophagy; BIOLOGICAL MARKERS; BIOLOGICAL RADIATION EFFECTS; BRAIN; DRUG DELIVERY; Endothelial cells; ENDOTHELIUM; INHIBITION; Ionizing radiation; IONIZING RADIATIONS; IRRADIATION; MALFORMATIONS; MEMBRANE PROTEINS; MITOCHONDRIA; NEOPLASMS; PDCE2; PHENOBARBITAL; Senescence; Vascular targeting
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2021.112688

Radiation has been proposed as a priming agent to induce discriminatory luminal biomarkers for vascular targeting and drug delivery in disorders such as brain arteriovenous malformations and cancers. We previously observed ectopic expression of intracellular proteins such as mitochondrial PDCE2 on irradiated endothelium in animal models. In this study we examined the mechanism of PDCE2 trafficking in human endothelial cells to better understand its suitability as a vascular target. Ionizing radiation induced PDCE2 surface localization in association with accumulation of autophagosome markers (L3CB and p62) indicative of late-stage inhibition of autophagic flux. This effect was abolished in the presence of Rapamycin, an autophagy-inducer, but replicated in the presence of Bafilomycin A, an autophagy blocker. PDCE2 co-localized with lysosomal markers of the canonical degradative autophagy pathway in response to radiation but also with recycling endosomes and SNARE proteins responsible for autophagosome-plasma membrane fusion. These findings demonstrate that radiation-induced blockade of autophagic flux stimulates redirection of intracellular molecules such as PDCE2 to the cell surface via a non-canonical secretory autophagy pathway. Intracellular membrane proteins trafficked in this way could provide a unique pool of radiation biomarkers for therapeutic drug delivery. •Radiation induces ectopic endothelial surface exposure of mitochondrial PDCE2.•PDCE2 translocation is associated with late-stage inhibition of autophagic flux.•Radiation damage overloads the degradative lysosomal pathway of autophagy.•PDCE2 trafficking occurs via autophagosomes and non-canonical secretory autophagy.•Surface PDCE2 provides a novel target for radiation-guided vascular drug delivery.