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The Autophagy Receptor SQSTM1/P62 Mediates Anti-Inflammatory Actions of the Selective NR3C1/ Glucocorticoid Receptor Modulator Compound a (Cpda) in Macrophages

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The Autophagy Receptor SQSTM1/P62 Mediates Anti-Inflammatory Actions of the Selective NR3C1/ Glucocorticoid Receptor Modulator Compound a (Cpda) in Macrophages Autophagy ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20 The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/ glucocorticoid receptor modulator compound A (CpdA) in macrophages Viacheslav Mylka, Julie Deckers, Dariusz Ratman, Lode De Cauwer, Jonathan Thommis, Riet De Rycke, Francis Impens, Claude Libert, Jan Tavernier, Wim Vanden Berghe, Kris Gevaert & Karolien De Bosscher To cite this article: Viacheslav Mylka, Julie Deckers, Dariusz Ratman, Lode De Cauwer, Jonathan Thommis, Riet De Rycke, Francis Impens, Claude Libert, Jan Tavernier, Wim Vanden Berghe, Kris Gevaert & Karolien De Bosscher (2018) The autophagy receptor SQSTM1/p62 mediates anti- inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages, Autophagy, 14:12, 2049-2064, DOI: 10.1080/15548627.2018.1495681 To link to this article: https://doi.org/10.1080/15548627.2018.1495681 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 14 Sep 2018. Submit your article to this journal Article views: 907 View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kaup20 AUTOPHAGY 2018, VOL. 14, NO. 12, 2049–2064 https://doi.org/10.1080/15548627.2018.1495681 RESEARCH PAPER - BASIC SCIENCE The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages Viacheslav Mylkaa,c,d, Julie Deckersa,c,d,f, Dariusz Ratmana,c,d, Lode De Cauwera,c,d, Jonathan Thommisa,c,d, Riet De Ryckef, g,h,i, Francis Impensc,d,j, Claude Libertf,g, Jan Tavernierb,c,d, Wim Vanden Berghee, Kris Gevaertc,d, and Karolien De Bosschera,c,d aReceptor Research Laboratories, Nuclear Receptor Lab, Ghent University, Ghent, Belgium; bReceptor Research Laboratories, Cytokine Receptor Lab, Ghent University, Ghent, Belgium; cDepartment of Biochemistry, VIB-UGent Center for Medical Biotechnology, Ghent, Belgium; dDepartment of Biochemistry, Ghent University, Ghent, Belgium; ePPES lab Protein Science, Proteomics & Epigenetic Signaling, Department Biomedical Sciences - University of Antwerp, Wilrijk, Belgium; fInflammation Research Center, VIB, Ghent University, Ghent, Belgium; gDepartment of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; hDepartment of Plant Systems Biology, VIB, Ghent, Belgium; iDepartment of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium; jVIB Proteomics Core, VIB, Ghent, Belgium ABSTRACT ARTICLE HISTORY Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorti- Received 15 September 2017 coids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified Revised 14 June 2018 as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) Accepted 27 June 2018 modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side KEYWORDS effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone Autophagy; autophagy (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages receptors; CpdA; using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not glucocorticoids; NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting inflammation; NFE2L2/NRF2; the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone SQSTM1/p62 recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy character- istics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechan- isms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy. Introduction systemic treatment with GCs is associated with acquired resis- tance to treatment, hypertension, osteoporosis and increased Glucocorticoids (GCs) are widely used to treat different glucose levels leading to diabetes. Selective NR3C1 modulators inflammatory diseases including rheumatoid arthritis and are studied as potential tools to solve this problem [8]. Using in asthma [1–3]. The natural (cortisol) and synthetic (e.g., dex- vitro and in vivo models, the dissociative nonsteroidal selective amethasone) glucocorticoids are known ligands of NR3C1/ NR3C1 modulator compound A (CpdA) was shown to exhibit glucocorticoid receptor (nuclear receptor subfamily 3, group an inflammation-suppressive effect, largely in the absence of the C, member 1). These glucocorticoids bind NR3C1 in the aforementioned side effects [9–13]. CpdA is a synthetic analog of cytoplasm leading to its translocation to the nucleus where the plant-derived hydroxy phenyl aziridine precursor [14]. it functions as a transcription factor. Activated NR3C1 can Recently, it was reported that CpdA can target the NFKB path- upregulate the transcription of different genes involved in way via a NR3C1-independent mechanism [13,15]. However, metabolism such as PCK1, TAT, G6PC and some anti-inflam- how a CpdA-mediated NR3C1-independent mechanism may matory genes such as TSC22D3/GILZ and DUSP1 by binding work and which proteins are necessary for the anti-inflamma- to NR3C1 response elements (GRE), a process known as tory action of CpdA remain largely unknown. transactivation [4,5]. Also, NR3C1 can transrepress pro- NFE2L2 (nuclear factor, erythroid derived 2, like 2) is a tran- inflammatory genes such as IL6, CCL2, and TNF via tethering scription factor responsible for the regulation of cellular redox to NFKB and AP-1 (FOS/JUN) complexes, or via direct bind- balances and for the protective antioxidant and phase II detoxifi- ing to negative GREs [6,7]. cation response [16,17]. NFE2L2 is tethered to KEAP1, which is GCs remain the most common prescribed anti-inflammatory highly enriched in cysteine residues and gets continuously ubiqui- drugs despite their possible severe side effects. Prolonged tinated and degraded by the proteasome. Upon oxidative stress or CONTACT Karolien De Bosscher [email protected] © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 2050 V. MYLKA ET AL. treatment with NFE2L2 inducers, NFE2L2 escapes from KEAP1 CpdA (10 μM) compared to DEX (1 μM) is in accord with the retention and translocates to the nucleus where it heterodimerizes effective in vitro anti-inflammatory dose of this nonsteroidal with small MAF proteins to transactivate genes with antioxidant compound, as established previously [14]. response elements (AREs) in their promoters, such as HMOX1, As a validation of the inflammatory stimuli and the accuracy NQO1 and TXNRD1.AutophagyreceptorsSQSTM1 and of this method, many classic inflammatory proteins, including CALCOCO2/NDP52 also have AREs in their promoters and can among others IL1B, NOS2, ICAM1, and NFKB2 were found to be regulated by NFE2L2 [17,18]. Moreover, SQSTM1 can act as an be significantly upregulated in LPS-treated cells compared to activator of NFE2L2 via the inactivation of KEAP1 [19,20]. As an solvent (non-induced [NI]) (Fig. S1B). In total, over 2,760 pro- autophagy receptor, SQSTM1 binds to ubiquitinated cargo sub- teins were quantified by shotgun proteomics, and a statistical strates and, by interaction with the phagophore-bound analysis comparing cells treated with CpdA + LPS versus LPS MAP1LC3/LC3 protein, targets them for degradation in a process alone revealed 4 significantly (p < 0.01) upregulated and 12 known as autophagy [21,22]. significantly downregulated proteins (Figure 1B). Ingenuity The search for factors that underlie the anti-inflammatory Pathway Analysis (IPA®) of these 16 proteins assigned 13 hereof propertiesofCpdAwillnotonlyhelptoclarifythedebated to the ‘Infectious Diseases, Cell-To-Cell Signaling and NR3C1 transrepression/transactivation paradigm [23], but might Interaction, Hematological Disease’ network (Figure 1C). also contribute to the discovery of alternative and safer anti- Among these proteins, SQSTM1 and HMOX1 caught our atten- inflammatory drugs. By using a shotgun mass spectrometry ana- tion because of a common transcription regulator, NFE2L2 [26]. lysis, we identified SQSTM1 and HMOX1 as significantly upregu- Because these proteins were not upregulated in the DEX+ LPS vs lated proteins following CpdA treatment of murine bone marrow- LPS set-up (Figure 1D), we considered them as potential candi- derived macrophages (BMDMs) under inflamed cellular condi- dates to explain the ability of CpdA to suppress inflammation, tions (LPS). We hypothesized that SQSTM1 and/or other mem- possibly independently from NR3C1, in a LPS-induced
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