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Mediated Signaling − Lectin Receptor USP15 Deubiquitinates CARD9 to Downregulate C-Type

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Mediated Signaling − Lectin Receptor USP15 Deubiquitinates CARD9 to Downregulate C-Type USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor−Mediated Signaling Wenting Xu, Jason S. Rush, Daniel B. Graham, Zhifang Cao and Ramnik J. Xavier Downloaded from ImmunoHorizons 2020, 4 (10) 670-678 doi: https://doi.org/10.4049/immunohorizons.2000036 http://www.immunohorizons.org/content/4/10/670 This information is current as of September 26, 2021. http://www.immunohorizons.org/ Supplementary http://www.immunohorizons.org/content/suppl/2020/10/22/4.10.670.DCSup Material plemental References This article cites 42 articles, 6 of which you can access for free at: http://www.immunohorizons.org/content/4/10/670.full#ref-list-1 Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: by guest on September 26, 2021 http://www.immunohorizons.org/alerts ImmunoHorizons is an open access journal published by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. ISSN 2573-7732. RESEARCH ARTICLE Innate Immunity USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor–Mediated Signaling Wenting Xu,*,†,‡,1 Jason S. Rush,§ Daniel B. Graham,*,†,§ Zhifang Cao,*,†,§ and Ramnik J. Xavier*,†,§ *Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; †Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Downloaded from ‡Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; and §Broad Institute of MIT and Harvard, Cambridge, MA 02142 http://www.immunohorizons.org/ ABSTRACT Posttranslational modifications are efficient means to rapidly regulate protein function in response to a stimulus. Although ubiquitination events and the E3 ubiquitin ligases involved are increasingly characterized in many signaling pathways, their regulation by deubiquitinating enzymes remains less understood. The C-type lectin receptor (CLR) signaling adaptor CARD9 was previously reported to be activated via TRIM62-mediated ubiquitination. In this study, we identify the deubiquitinase USP15 as a novel regulator of CARD9, demonstrating that USP15 constitutively associates with CARD9 and removes TRIM62-deposited ubiquitin marks. Furthermore, USP15 knockdown and knockout specifically enhance CARD9-dependent CLR signaling in both mouse and human immune cells. Altogether, our study identifies a novel regulator of innate immune signaling and provides a blueprint for the identification of additional deubiquitinases that are likely to control these processes. ImmunoHorizons, 2020, 4: 670–678. by guest on September 26, 2021 INTRODUCTION (10–14), although it remains unclear whether CARD9 is important in defense against microbes other than fungi and microalgae in Human genetic studies have uncovered that CARD9 is important humans. for immune-microbial interactions at mucosal surfaces, as CARD9 In IBD, CARD9 variants have been associated with both risk polymorphisms are associated with disorders such as immunode- and protection. A rare splicing mutation IVS11+1G.C, resulting in ficiency, inflammatory bowel diseases (IBD), and increased a C-terminally truncated CARD9, plays a protective role against susceptibility to fungal infection (1–3). To date, more than two IBD and ankylosing spondylitis (15, 16). A common coding variant, dozen CARD9-coding mutations have been reported in clinical CARD9 S12N (single-nucleotide polymorphism rs4077515), re- studies to predispose individuals to diseases associated with fungal sults in higher CARD9 mRNA expression (17) and is associated or microalgal infection (4–9). CARD9 has also been reported to be with increased risk of IBD (15, 17), ankylosing spondylitis (18), Ig critical during bacterial and viral infections in mouse models A nephropathy (19), and primary sclerosing cholangitis (20). This Received for publication May 13, 2020. Accepted for publication October 7, 2020. Address correspondence and reprint requests to: Dr. Zhifang Cao and Dr. Ramnik J. Xavier, Massachusetts General Hospital, 185 Cambridge Street, Simches 7, Boston, MA 02114. E-mail addresses: [email protected] (Z.C.) and [email protected] (R.J.X.) ORCIDs: 0000-0003-3019-2763 (Z.C.); 0000-0002-5630-5167 (R.J.X.). 1Current address: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. This work was supported by funding from the Helmsley Charitable Trust and the National Institutes of Health (Grant AI137325 to R.J.X.). W.X. was supported by the China Scholarship Council. R.J.X. and Z.C. conceived the project. W.X., J.S.R., and Z.C. performed experiments. R.J.X., Z.C., and D.B.G. supervised the project. R.J.X. and Z.C. wrote the manuscript. All authors discussed the results and commented on the manuscript. Abbreviations used in this article: BMDC, bone marrow–derived dendritic cell; CBM, CARD9–BCL10–MALT1; CLR, C-type lectin receptor; HA, hemagglutinin; IBD, inflammatory bowel disease; KO, knockout; sgRNA, single-guide RNA; shRNA, short hairpin RNA; TDM, trehalose 6,69-dimycolate; USP15, ubiquitin-specific peptidase 15; WGP, whole glucan particle. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY 4.0 Unported license. Copyright © 2020 The Authors 670 https://doi.org/10.4049/immunohorizons.2000036 ImmunoHorizons is published by The American Association of Immunologists, Inc. ImmunoHorizons USP15 DEUBIQUITINATES CARD9 TO DOWNREGULATE CLR SIGNALING 671 variant, however, also appears to have protective effects in some downstream of CARD9, suggesting that it is an important contexts, such as primary immune thrombocytopenia (21). regulator of this innate immune signaling pathway. Mechanistically, when expressed at equivalent levels, the S12N allele enhances CARD9-mediated cytokine production in murine bone marrow–derived dendritic cells (BMDCs) stimulated with MATERIALS AND METHODS fungal products relative to the wild-type allele (22), indicating that S12N is a gain-of-function mutant. CARD9 S12N reportedly Reagents and plasmids enhances IL-5 production in macrophages; accordingly, PBMCs Whole glucan particles (WGP) were purchased from InvivoGen from three S12N homozygous patients with allergic bronchopul- (catalog no. tlrl-wgp). TDM was obtained from Enzo Life Sci- monary aspergillosis produced higher levels of IL-5 than those ences (catalog no. AL-581-210-M001). TDM was dissolved in from an allergic bronchopulmonary aspergillosis patient carrying chloroform/methanol/water(90:10:1, 1 mg/ml) and further diluted wild-type CARD9 (23). with isopropanol. LPS was purchased from InvivoGen (catalog no. CARD9 is an essential component of innate immune signaling tlrl-peklps). through multiple C-type lectin receptors (CLRs), such as Dectin-1, Lentivirus-based short hairpin RNA (shRNA) constructs were Dectin-2, Dectin-3, and Mincle (2). These receptors are generally generated in a pLKO.1 vector by the Genetic Perturbation Platform Downloaded from expressed on myeloid cells and recognize a broad range of fungal at the Broad Institute of MIT and Harvard. A lentiviral vector cell wall components (24). Mincle is additionally activated by pCDH-CMV from Addgene (no. 72265) was used to generate lenti- nuclear protein SAP130 released from damaged cells (25) and based USP15 constructs with a puromycin–T2A–3xHA tag in the trehalose 6,69-dimycolate (TDM; also known as cord factor) N terminus. All other constructs were either cloned into a pCMV present in the cell membranes of mycobacteria (26), suggesting a vector (Clontech Laboratories) or pcDNA4/TO–FLAG–StrepII as http://www.immunohorizons.org/ broad role for CLRs in innate immune recognition of fungi, described previously (22). USP15 variants were originally ampli- damaged cells, and certain bacteria. Upon engagement, CLRs fied from a Clontech Laboratories immune cDNA panel and activate the tyrosine kinase Syk to facilitate the formation of the subcloned into indicated tagged vectors by PCR. CARD9–BCL10–MALT1 (CBM) complex (27), which is essential for downstream NF-kB signaling and related immune responses. Immunoprecipitation and Western blotting Notably, CBM architecture in signaling cascades is not limited to The experimental methods were previously described in detail CARD9 in myeloid cells but also exists with CARD10 in (22). Briefly, cells were lysed in standard lysis buffer (50 mM Tris- nonhematopoietic cells, CARD11 in lymphoid cells, and CARD14 HCl [pH 7.5], 150 mM NaCl, 0.5 mM EDTA, 1% Nonidet P-40, in keratinocytes. Although these CBM complexes are highly Halt phosphatase inhibitor single-use mixture [Pierce Biotech], specific to cell types and stimuli, their activity likely involves and protease inhibitor tablets [Roche Diagnostics]). For immuno- by guest on September 26, 2021 similar regulatory events. precipitation of Flag–StrepII-tagged protein, cell lysates were Posttranslational modifications are known to directly regulate incubated with StrepII Sepharose beads (catalog no. 2-1201-010; the assembly of CBM complexes. In the case of CARD9, IBA) for 1 h at 4°C. For immunoprecipitation of endogenous phosphorylation directly regulates the formation of the CBM CARD9 in BMDCs, cell lysates were incubated with anti-CARD9 complex: protein kinase C d phosphorylates CARD9 on T231, Ab or control IgG overnight, followed by pulldown with protein facilitating
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