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Pharmacological Targeting of the ER-Resident Chaperones GRP94 or Cyclophilin B Induces Secretion of IL-22 Binding Protein Isoform-1 (IL-22BPi1)

1
Neurogenomiks Group, Department of Neuroscience, University of the Basque Country (UPV/EHU), 48490 Leioa, Spain
2
IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(10), 2440; https://doi.org/10.3390/ijms20102440
Received: 29 April 2019 / Revised: 14 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
(This article belongs to the Section Molecular Biology)
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Abstract

Of the three interleukin-22 binding protein (IL-22BP) isoforms produced by the human IL22RA2 gene, IL-22BPi2 and IL-22BPi3 are capable of neutralizing IL-22. The longest isoform, IL-22BPi1, does not bind IL-22, is poorly secreted, and its retention within the endoplasmic reticulum (ER) is associated with induction of an unfolded protein response (UPR). Therapeutic modulation of IL-22BPi2 and IL-22BPi3 production may be beneficial in IL-22-dependent disorders. Recently, we identified the ER chaperones GRP94 and cyclophilin B in the interactomes of both IL-22BPi1 and IL-22BPi2. In this study, we investigated whether secretion of the IL-22BP isoforms could be modulated by pharmacological targeting of GRP94 and cyclophilin B, either by means of geldanamycin, that binds to the ADP/ATP pocket shared by HSP90 paralogs, or by cyclosporin A, which causes depletion of ER cyclophilin B levels through secretion. We found that geldanamycin and its analogs did not influence secretion of IL-22BPi2 or IL-22BPi3, but significantly enhanced intracellular and secreted levels of IL-22BPi1. The secreted protein was heterogeneously glycosylated, with both high-mannose and complex-type glycoforms present. In addition, cyclosporine A augmented the secretion of IL-22BPi1 and reduced that of IL-22BPi2 and IL-22BPi3. Our data indicate that the ATPase activity of GRP94 and cyclophilin B are instrumental in ER sequestration and degradation of IL-22BPi1, and that blocking these factors mobilizes IL-22BPi1 toward the secretory route. View Full-Text
Keywords: IL-22BP; isoform; IL22RA2; ER; UPR; GRP94; gp96; GRP78; BiP; cyclophilin; geldanamycin; cyclosporin A IL-22BP; isoform; IL22RA2; ER; UPR; GRP94; gp96; GRP78; BiP; cyclophilin; geldanamycin; cyclosporin A
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Gómez-Fernández, P.; Urtasun, A.; Astobiza, I.; Mena, J.; Alloza, I.; Vandenbroeck, K. Pharmacological Targeting of the ER-Resident Chaperones GRP94 or Cyclophilin B Induces Secretion of IL-22 Binding Protein Isoform-1 (IL-22BPi1). Int. J. Mol. Sci. 2019, 20, 2440.

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