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 variants are present in mammals, displaying high sequence similarity. All three can prevent the secretion of KDEL-bearing clients. However, their diverse tissue distribution and the high phylogenetic conservation of the differences suggest functional specialization. Accordingly, we show here that while KDELR2 plays a major role in client retrieval, KDELR1 and KDELR3 regulate the production of AGR2, a key assistant of mucin folding, in opposite ways. AGR2 transcripts increase dramatically upon silencing KDELR3 but decrease when KDELR1 is downregulated. Silencing ERp44, but no other ER residents, phenocopies KDELR3 knockdown, suggesting that AGR2 regulation depends on ERp44-KDELR3 interactions. Our findings identify a novel regulatory circuit, distinct from the unfolded protein response, that controls the molecular composition of the early secretory pathway based on specific interactions between KDELRs and ER residents.

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Publication Details

Journal
Cellular and Molecular Life Sciences
Published
2026-02-18
DOI
https://doi.org/10.1007/s00018-025-06049-1
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Kenji Inaba, Michele Sallese, Yuta Amagai, Masaki Matsumoto et al.
Cellular and Molecular Life Sciences
Cellular transport and secretion
article

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

Kenji Inaba, Michele Sallese, Yuta Amagai, Masaki Matsumoto, Tiziana Tempio, Federica Cecilia Palazzo, Roberto Sitia, Xue Han, Matthias Johannes Feige, Tiziana Anelli, Caterina Valetti, Marco Dalla Torre, Jose Garcia Manteiga
article en

Abstract

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 variants are present in mammals, displaying high sequence similarity. All three can prevent the secretion of KDEL-bearing clients. However, their diverse tissue distribution and the high phylogenetic conservation of the differences suggest functional specialization. Accordingly, we show here that while KDELR2 plays a major role in client retrieval, KDELR1 and KDELR3 regulate the production of AGR2, a key assistant of mucin folding, in opposite ways. AGR2 transcripts increase dramatically upon silencing KDELR3 but decrease when KDELR1 is downregulated. Silencing ERp44, but no other ER residents, phenocopies KDELR3 knockdown, suggesting that AGR2 regulation depends on ERp44-KDELR3 interactions. Our findings identify a novel regulatory circuit, distinct from the unfolded protein response, that controls the molecular composition of the early secretory pathway based on specific interactions between KDELRs and ER residents.

Cellular and Molecular Life SciencesVol. 83(1)
Kyushu University (JP), Vita-Salute San Raffaele University (IT), University of Chieti-Pescara (IT), IRCCS Ospedale San Raffaele (IT), Technical University of Munich (DE), Niigata University (JP), University of Genoa (IT)
Japan Agency for Medical Research and Development, Ministero dell’Istruzione, dell’Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Core Research for Evolutional Science and Technology
Life in Land
Openalex Percentile: Top 54%
Cellular transport and secretion
DOIOpen Access PDFOpenAlex
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