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The Atypical Chemokine Receptor ACKR3/CXCR7 Is a Broad-Spectrum Scavenger for Opioid Peptides

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The Atypical Chemokine Receptor ACKR3/CXCR7 Is a Broad-Spectrum Scavenger for Opioid Peptides University of Southern Denmark The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Meyrath, Max; Szpakowska, Martyna; Zeiner, Julian; Massotte, Laurent; Merz, Myriam P.; Benkel, Tobias; Simon, Katharina; Ohnmacht, Jochen; Turner, Jonathan D.; Krüger, Rejko; Seutin, Vincent; Ollert, Markus; Kostenis, Evi; Chevigné, Andy Published in: Nature Communications DOI: 10.1038/s41467-020-16664-0 Publication date: 2020 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Meyrath, M., Szpakowska, M., Zeiner, J., Massotte, L., Merz, M. P., Benkel, T., Simon, K., Ohnmacht, J., Turner, J. D., Krüger, R., Seutin, V., Ollert, M., Kostenis, E., & Chevigné, A. (2020). The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications, 11, [3033]. https://doi.org/10.1038/s41467-020-16664-0 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 07. Oct. 2021 ARTICLE https://doi.org/10.1038/s41467-020-16664-0 OPEN The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Max Meyrath1,9, Martyna Szpakowska 1,9, Julian Zeiner2, Laurent Massotte3, Myriam P. Merz1, Tobias Benkel 2,4, Katharina Simon2, Jochen Ohnmacht 5,6, Jonathan D. Turner 1, Rejko Krüger5,7, ✉ Vincent Seutin3, Markus Ollert1,8, Evi Kostenis 2 & Andy Chevigné 1 Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress 1234567890():,; by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3’s negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid- related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity. 1 Department of Infection and Immunity, Luxembourg Institute of Health (LIH), rue Henri Koch 29, L-4354 Esch-sur-Alzette, Luxembourg. 2 Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany. 3 Neurophysiology Unit, GIGA Neurosciences, University of Liège, avenue de l’hopital, B-4000 Liège, Belgium. 4 Research Training Group 1873, University of Bonn, Bonn, Germany. 5 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, avenue du Swing 6, L-4367 Belvaux, Luxembourg. 6 Department of Life Sciences and Medicine, University of Luxembourg, avenue du Swing 6, L-4367 Belvaux, Luxembourg. 7 Transversal Translational Medicine, Luxembourg Institute of Health (LIH), rue Thomas Edison 1A-B, L-1445 Strassen, Luxembourg. 8 Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, 5000 Odense, Denmark. 9These authors contributed equally: Max Meyrath, Martyna Szpakowska. ✉ email: [email protected] NATURE COMMUNICATIONS | (2020) 11:3033 | https://doi.org/10.1038/s41467-020-16664-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16664-0 pioid receptors are G protein-coupled receptors (GPCRs) In this study, we show that ACKR3 is abundantly expressed in Othat play a central role in reward processing, euphoria, the same brain regions as the classical opioid receptors and that, analgesia, stress, anxiety, and depression. The family besides BAM22, ACKR3 is activated by a large array of endo- consists of three classical receptors: mu (μ or MOR), delta (δ or genous opioid peptides found in the CNS and immune cells, DOR), and kappa (κ or KOR) and a fourth, non-classical noci- including those from the enkephalin, dynorphin and nociceptin ceptin receptor (NOP, also known as orphanin FQ receptor)1,2. families. However, contrary to the other four opioid receptors but The classical receptors are activated by three major families of in keeping with its atypical receptor features, ACKR3 is unable to opioid peptides, namely endorphins, enkephalins, and dynor- activate canonical G protein signaling. Instead, it exclusively phins, each showing a preference for one or two families, while recruits arrestins in response to opioid peptides. We show that the non-classical NOP receptor shows a high affinity and selec- ACKR3 acts as a scavenger towards this family of neuromodu- tivity towards nociceptin3. All endogenous opioid peptides derive lators, thus regulating their availability for signaling through the from proteolytic cleavage of large protein precursors and are established opioid receptors, similarly to its role in chemokine mainly produced in the central nervous system (CNS), but also in gradient modulation. Hence, we propose ACKR3 as a pro- the adrenal and pituitary gland and by several types of immune miscuous atypical opioid receptor (AOR) that functions as a cells4,5. With some exceptions, these ligands trigger downstream scavenger receptor to regulate not only the abundance of che- receptor signaling via G proteins, which is followed by arrestin mokines but also of opioid peptides. recruitment, leading to receptor desensitization, and internali- zation6,7. Opioid receptors are established drug targets for non- peptide opioids such as morphine, fentanyl, or naloxone. These Results opioid receptor modulators are the most widely used analgesics in ACKR3 is activated by a broad range of opioid peptides.Ina the clinic but their use is associated with severe drawbacks like recent study, we suggested that the proenkephalin-derived peptide tolerance, dependence, or respiratory depression, which were BAM22 shares structural and functional features important for proposed to be linked to ligand and receptor bias towards arrestin ACKR3 binding and activation with the N terminus of chemokine recruitment8–10. Thus, a better understanding of opioid receptor ligands35. Given that all endogenous opioid peptides show signaling regulation and bias as well as new strategies to modulate remarkable sequence homologies including the F/YGGFL/M motif opioid receptors with less adverse effects are not only timely but at their N termini, as well as several positively charged residues also urgently needed, especially considering the current opioid throughout the sequence (Table 1), we wondered whether BAM22 crisis. and the related peptides are the only opioid peptides able to Opioid receptor expression, signaling, and desensitization are activate ACKR3. Therefore, we screened a library of 58 opioid furthermore influenced by their interactions with other GPCRs, peptides (5 µM, Supplementary Table 1) for their ability to induce notably chemokine receptors11–13. Chemokine receptors bind to β-arrestin-2 recruitment to ACKR3 (indicative of ACKR3 activa- chemokines, which are small (8–14 kDa) secreted chemo- tion), and, additionally to CXCR4 and CXCR3, two classical attractant cytokines, regulating cellular processes like migration, chemokine receptors sharing ligands with ACKR3, which served adhesion, and growth and thereby playing a crucial role in as negative controls. Besides BAM22, BAM18, and Peptide E inflammatory and developmental processes14,15. To date, nearly previously reported as ACKR3 ligands34, our screening revealed 50 chemokines and 20 classical chemokine receptors have been that numerous other opioid peptides are capable of inducing β- identified in humans16,17. Similar to the opioid receptor–ligand arrestin-2 recruitment to ACKR3. These included adrenorphin, network, many chemokine receptors recognize multiple chemo- another proenkephalin-derived peptide, but also peptides from the kines, and, vice versa, many chemokines activate more than one nociceptin and dynorphin families (Fig. 1a). Endorphins and receptor. Notably, within this network, a small subfamily of endomorphins, however, did not activate ACKR3. None of these receptors, called atypical chemokine receptors (ACKRs), plays peptides acted as ACKR3 antagonist (Supplementary Fig. 1a) or essential regulatory roles. ACKRs bind chemokines without induced β-arrestin-2 recruitment to CXCR4 or CXCR3 (Fig. 1a). triggering G protein signaling but instead participate in chemo- We then sought to further characterize the interactions of the tactic events by
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