Coordinated transcriptional networks program organelle expansion and metabolic flows for high endothelial morphology and function.

High endothelial cells (HECs) control lymphocyte homing for adaptive immunity. They are defined by plump morphology, reflecting endoplasmic reticulum (ER) and Golgi expansion, and are by display of sulfo-sialomucins of the peripheral node addressin (PNAd) critical for lymphocyte recruitment. How these features are linked was unclear. Here, we found that HEC genes for sulfoglycoprotein synthesis and organelle expansion are enriched in binding motifs for ER stress-response transcription factors XBP1 and CREB3L2. These factors bound and drove expression from conserved elements in sulfo- and fucosyl-transferase and transporter genes for PNAd synthesis. Endothelial-specific deletion of Xbp1, or pharmacologic inhibition of enzymes for XBP1 or CREB3L2 activation, impaired PNAd expression, flattened HECs, reduced lymphocyte recruitment, and prevented HEC induction during inflammation. Parallel programs were found in intestinal goblet cells, suggesting conserved mechanisms coupling organelle scaling with sulfoglycoprotein production. Thus, HECs employ adaptive ER programs to build the biosynthetic infrastructure driving their morphology and function.