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Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors

M. Bosakova, SP. Abraham, D. Wachtell, JT. Zieba, A. Kot, A. Nita, AA. Czyrek, A. Koudelka, VC. Ursachi, Z. Feketova, G. Rico-Llanos, K. Svozilova, P. Kocerova, B. Fafilek, T. Gregor, J. Kotaskova, I. Duran, P. Vanhara, M. Doubek, J. Mayer, K....

. 2025 ; 23 (1) : 209. [pub] 20250430

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25016011

Grant support
NIH AR 006124, NIH P01 HD070394 NIH HHS - United States
Programme EXCELES, ID Project No. LX22NPO5102 CCR NIH HHS - United States
CZ.02.2.69/0.0/0.0/19_073/0016943 IGA MUNI
FNBr, 65269705 MH CZ - DRO
Geisman award Osteogenesis Imperfecta Foundation
GA21-11585S Czech Science Foundation
Praemium Academiae Czech Academy of Sciences
LUAUS23295 Ministry of Education, Youth and Sports of the Czech Republic
GF21-26400K Czech Science Foundation
NU23-10-00550 Agency for Healthcare Research of the Czech Republic
P01 HD070394 NICHD NIH HHS - United States

Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.

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$a Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.
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