A regulatory circuit operated by KDELR1 and KDELR3 fine-tunes the composition of the early secretory pathway

KDEL receptors (KDELRs) prevent the secretion of soluble chaperones and enzymes meant to reside in the endoplasmic reticulum. While a single KDELR exists in yeast (ERD2), three isoforms are present in mammals, displaying high sequence similarity (73-83%). However, the phylogenetic conservation of the differences and the diverse tissue distribution of the three KDELRs suggest functional specialization. We show here that, while all three receptors can prevent the secretion of KDEL-bearing clients, KDELR1 and KDELR3 regulate in opposite ways the production of AGR2, a key assistant of mucin folding. AGR2 transcripts increase dramatically upon silencing KDELR3 but decrease when KDELR1 is downregulated. Silencing ERp44, but not other ER residents, phenocopies KDELR3 knockdown, suggesting that AGR2 regulation depends on ERp44-KDELR3 interactions. Our findings identify a novel regulatory circuit that controls the molecular composition of the early secretory pathway based on specific interactions between KDELRs and ER residents.