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Occludin protects secretory cells from ER stress by facilitating SNARE-dependent apical protein exocytosis

Significance Despite being the first tight junction (TJ) component discovered and numerous in vitro studies showing its TJ-related functions, Ocln has remained elusive regarding its physiological functions because Ocln null mice develop normally. Here we demonstrate that Ocln null mammary gland epithelium has intact TJ integrity, which argues against it being an essential TJ component as previously expected; rather, Ocln plays a role in regulating protein secretion by binding to SNARE components. Ocln mutant milk-producing cells exhibit defective protein secretion and augmented endoplasmic reticulum stress and unfolded protein response, ultimately leading to protein expression shutdown and lactation failure in mutant mice. Our results thus shed important light on the essential physiological functions of Ocln in the vertebrate epithelium. Tight junctions (TJs) are fundamental features of both epithelium and endothelium and are indispensable for vertebrate organ formation and homeostasis. However, mice lacking Occludin (Ocln) develop relatively normally to term. Here we show that Ocln is essential for mammary gland physiology, as mutant mice fail to produce milk. Surprisingly, Ocln null mammary glands showed intact TJ function and normal epithelial morphogenesis, cell differentiation, and tissue polarity, suggesting that Ocln is not required for these processes. Using single-cell transcriptomics, we identified milk-producing cells (MPCs) and found they were progressively more prone to endoplasmic reticulum (ER) stress as protein production increased exponentially during late pregnancy and lactation. Importantly, Ocln loss in MPCs resulted in greatly heightened ER stress; this in turn led to increased apoptosis and acute shutdown of protein expression, ultimately leading to lactation failure in the mutant mice. We show that the increased ER stress was caused by a secretory failure of milk proteins in Ocln null cells. Consistent with an essential role in protein secretion, Occludin was seen to reside on secretory vesicles and to be bound to SNARE proteins. Taken together, our results demonstrate that Ocln protects MPCs from ER stress by facilitating SNARE-dependent protein secretion and raise the possibility that other TJ components may participate in functions similar to Ocln.