Common Gene Networks Orchestrate Organelle Architecture and Inter-Organelle Metabolic Flows for Mucin Production in High Endothelial and Goblet Cells

High endothelial cells (HECs) and intestinal goblet cells (GCs) are highly specialized through organelle expansion and metabolism for production of sulfated mucins essential for lymphocyte homing and mucosal defense, respectively. How these cells coordinate organelle architecture and biosynthetic pathways to support such demands remains poorly understood. Here, we show at single-cell resolution that HECs rely on gene regulatory networks driven by IRE1-XBP1 and CREB3L1/2 transcription factors. These networks upregulate enzymes and transporters that control inter-organelle metabolic fluxes for the step-wise assembly of sulfated O-glycan synthesis, while scaling the endoplasmic reticulum (ER) and Golgi apparatus, reinforcing cargo trafficking and organizing sequential glycosyltransferase deployment. Genetic and pharmacological perturbations show that these transcriptional circuits sustain lymph node HEC morphology and function in lymphocyte homing, and drive ectopic induction of HEV during inflammation. Parallel transcriptional networks operate in GCs. Together, our findings define a conserved regulatory logic that integrates metabolic pathways and organelle architecture to enable committed sulfo-mucin cell specialization across distinct tissue contexts. O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/660616v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@274d9borg.highwire.dtl.DTLVardef@5837b7org.highwire.dtl.DTLVardef@1b1d6bcorg.highwire.dtl.DTLVardef@88f256_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG Key pointsO_LISulfated O-glycan biosynthesis is coordinated through the integration of inter-organelle metabolic fluxes with organellar protein machineries in HECs and GCs. C_LIO_LIIRE1-XBP1 and CREB3L1/2 coordinate gene networks that orchestrate this integration in HECs and GCs. C_LIO_LIInhibiting XBP1 or CREB3L2 activation flattens HECs, reduces PNAd expression, and diminishes lymphocyte homing. C_LIO_LIXBP1 deletion disrupts metabolic fluxes required for PNAd synthesis, impairing HEC morphology, lymphocyte recruitment, and ectopic induction during inflammation. C_LI