Epithelial endocytosis is essential for tissue homeostasis. The current dogma is that all endocytotic mechanisms involve only single-membrane vesicles at the plasma membrane. Using occludin-null mice, we uncovered an undescribed LC3-associated junctional endocytosis mechanism that forms double-membrane paraphagosomes from the tight-junction paracellular membranes, which we termed “paraphagy”. We observed that paraphagy is more abundant in the male reproductive system than other mucosal systems. Paraphagy endocytoses APOJ-chaperoned lipophilic cargoes via binding to the surface low-affinity IgG-receptor FCGR2B and involves occludin-bound intracellular HDL-receptor ATP5B in the epididymis, the organ for sperm maturation. In this way, extracellular lipophilic signals are sensed and intracellular phagolysosomes are maintained. In this regard, occludin-null mice showed arrested paraphagy and impaired phagolysosome in proximal epididymis, accompanying APOJ accumulation and dysregulated luminal physiological microenvironment throughout epithelial cavity, and thereby male infertility. We propose that paraphagy-associated junctional endocytosis senses and absorbs the luminal lipophilic cargoes and confers epithelial health.
This work is supported by grants to WWS (NNSFC: 31871166; 82071704) and (SMCST: 17JC1420103; 19140903400), Center for Excellence in Molecular Cell Science (CAS), and ShanghaiTech University.
