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Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling

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Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling This information is current as Yoko K. Takada, Jessica Yu, Michiko Shimoda and of October 2, 2021. Yoshikazu Takada J Immunol published online 22 July 2019 http://www.jimmunol.org/content/early/2019/07/19/jimmun ol.1801630 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 22, 2019, doi:10.4049/jimmunol.1801630 The Journal of Immunology Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling Yoko K. Takada,*,† Jessica Yu,* Michiko Shimoda,* and Yoshikazu Takada*,† CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin a5b1 and CD40 simultaneously bind to CD40L. It is unclear if a5b1 and CD40 work together in CD40/CD40L signaling or how a5b1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of a5b1to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-kB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin a5b1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin avb3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that avb3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper- Downloaded from IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to a5b1 and avb3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that a5b1 and avb3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling. The Journal of Immunology, 2019, 203: 000–000. http://www.jimmunol.org/ D40 is a membrane-bound costimulatory protein that bind to the cytoplasmic tail of CD40 and can activate multiple belongs to the TNFR family, which is constitutively signaling cascades dependent on the TRAF family member that C expressed by B cells and dendritic cells, but upon cell binds and the cell type that is activated. The CD40 cytoplasmic activation, the protein is broadly expressed on hematopoietic cells, domain has a proximal TRAF-6 binding site and a more-distal including T cells, monocytes, and macrophages, but also on non- TRAF-2/3/5 binding site (7). The CD40–CD40L dyad is an im- hematopoietic cells, such as endothelial cells (1). CD40L is a TNF mune checkpoint regulator that promotes both humoral and cel- family member, which is expressed as a transmembrane form and lular immune responses by regulating the inflammatory phenotype released as a soluble form (sCD40L) by proteolytic cleavage, on of immune and nonimmune cells. Genetic and Ab-mediated in- by guest on October 2, 2021 both T cells and platelets. During inflammation, CD40L is also hibition of CD40 or CD40L successfully reduced disease burden expressed on B cells, dendritic cells, monocytes, macrophages, in experimental models of atherosclerosis, Crohn disease, psori- endothelial cells, and CNS resident cells. CD40L/CD40 interac- asis, rheumatoid arthritis, and experimental autoimmune enceph- tion is required for enhancing Ag-presenting functions of dendritic alomyelitis (1). CD40L’s critical role in T cell–dependent humoral cells, macrophages, and B cells; maturation of humoral responses; immune responses was demonstrated by patients with the hyper- and enhancement of effector T cell responses (2). Additional IgM syndrome type 1 (HIGM1) as well as by gene targeting in functions of CD40L include the initiation of inflammatory and mice. It has been believed that trimeric CD40L is biologically procoagulatory responses in vascular endothelial cells (3–5). active, but monomeric CD40L is not. sCD40L levels markedly CD40L is a key player in chronic autoimmune inflammatory increase in certain pathologic conditions (SLE and rheumatoid diseases, including systemic lupus erythematosus (SLE), diabetes, arthritis), but most of the increased sCD40L is monomeric (8). and chronic kidney disease (6). CD40-mediated signaling depends Integrins are a family of cell-surface ab receptor heterodimers on adaptor molecules, the TNFR-associated factors (TRAFs) that that bind to extracellular matrix ligands (e.g., fibronectin, fi- brinogen, and collagen), cell-surface ligands (e.g., ICAM-1 and *Department of Dermatology, School of Medicine, University of California, Davis, VCAM-1), and soluble ligands (e.g., growth factors) (9). Integrins Sacramento, CA 95817; and †Department of Biochemistry and Molecular Medicine, transduce signals inside the cells upon ligand binding and are School of Medicine, University of California, Davis, Sacramento, CA 95817 regulated by signals from inside the cells (inside-out signaling) Received for publication December 14, 2018. Accepted for publication June 24, (10). CD40L is known to bind to several integrins in addition to 2019. CD40. Previous reports suggest that integrins aIIbb3 (11), a5b1 This work was supported by a Science Translation and Innovative Research grant from a b the University of California, Davis and National Institutes of Health R33CA196445 and (12), and M 2 (13) bind to CD40L. Each of these integrins in- T32 HL007013. teracts with CD40L in a specific manner. aIIbb3 recognizes the Address correspondence and reprint requests to Prof. Yoshikazu Takada, Department KGD motif of CD40L (residues 115–117 of CD40L). a5b1 does of Dermatology and Department of Biochemistry and Molecular Medicine, Univer- not require the KGD motif. Mutations of the CD40-binding site sity of California, Davis School of Medicine, Research III Suite 3300, 4645 Second Avenue, Sacramento, CA 95817. E-mail address: [email protected] (Y145A, R203A, or Y145A/R203A double mutant) did not affect a b a b Abbreviations used in this article: CHO, Chinese hamster ovary; HIGM1, hyper-IgM 5 1-CD40L interaction (14), suggesting that 5 1 and CD40- syndrome type 1; sCD40L, soluble CD40L; SEAP, soluble embryonic alkaline phos- binding sites on CD40L are distinct. It has recently been reported phatase; SLE, systemic lupus erythematosus; TRAF, TNFR-associated factor; WT, that the N151A/Q166 mutation on the surface of trimeric CD40L wild-type. suppresses a5b1-mediated CD40L binding (15), but the a5b1- Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 binding site in CD40L has not been well defined. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801630 2 CD40L MUTANTS DEFECTIVE IN INTEGRIN BINDING ARE ANTAGONISTS The a5b1-mediated CD40L signaling has been reported in incubated for 1 h, and bound sCD40L was measured using HRP-conjugated malignant T cell leukemia cells (16). The binding of CD40L to anti-His. a5b1 induced antiapoptotic signals, promoted survival of ma- Cell viability assays lignant T cell leukemia, and facilitated tumor development and 3 4 propagation. CD40L binding to a5b1 activated key survival Ramos cells (2 10 cells per well) were serum starved overnight in serum-free media (RPMI 1640) and incubated with proteins (WT or proteins, such as p38 and ERK1/2 MAPKs, phosphoinositide mutant CD40L) for 24 h in a 96-well plate. Cell viability was measured 3 kinase (PI-3K), and Akt. sCD40L significantly inhibited Fas- by MTS assay using an AQueous Cell Proliferation Assay kit (Promega, mediated apoptosis in T cell leukemia-lymphoma cell lines, an Madison, WI). important hallmark of T cell survival during malignancy pro- Adhesion assays gression. The CD40L-triggered inhibition of the Fas-mediated cell death response is dependent on a suppression of caspase-8 Adhesion assays were performed as described previously (21). Briefly, to assess cell adhesion to immobilized CD40L, 96-well Immulon-2 microtiter cleavage (16). However, the specifics of integrin–CD40L inter- plates were coated with 100 ml of PBS containing sCD40L or its mutant action are not fully established, and the role of integrins in (20 mg/ml) and were incubated for 2 h at 37˚C. Remaining protein-binding CD40/CD40L signaling has been largely ignored. sites were blocked by incubating with PBS/0.1% BSA for 30 min at room In the current study, we present evidence that the a5b1-binding temperature. After being washed with PBS, CHO cells in 100 mlofDMEM site is located in the trimeric interface of CD40L by docking were added to the wells and incubated at 37˚C for 1 h. After unbound cells were removed by rinsing the wells with the medium used for adhesion simulation and mutagenesis studies. This suggests that, because assays, bound cells were quantified by measuring endogenous phosphatase the integrin-binding sites are cryptic in trimeric CD40L, mono- activity (21).
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