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App1: An Antiphagocytic Protein That Binds to Complement Receptors 3 and 2¹

Paola Stano^2,*, Virginia Williams^2,*, Maristella Villani^*, Eugene S. Cymbalyuk^*, Asfia Qureshi^*, Yuxiang Huang, Giulia Morace, Chiara Luberto^*, Stephen Tomlinson and Maurizio Del Poeta^3,*,,

^* Biochemistry and Molecular Biology, Microbiology and Immunology, and Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425; and Dipartimento di Sanita’ Pubblica, Microbiologia-Virologia, Universita’ degli Studi di Milano, Milan, Italy

In previous studies, we showed that the pathogenic fungus Cryptococcus neoformans (Cn) produces a specific and unique protein called antiphagocytic protein 1 (App1), which inhibits phagocytosis of Cn by alveolar macrophages (AMs). Phagocytosis of Cn by AMs occurs mainly through a complement- or Ab-mediated mechanism. Among AM receptors, complement receptor 3 (CR3) and FcR are the most common receptors involved in the phagocytic process. Because App1 inhibits phagocytosis of complement- but not Ab-coated erythrocytes, we investigated the role of CR3 in App1-macrophage interactions. We found that App1 binds to CR3 and if CR3 is absent from the surface of AMs, its antiphagocytic action is lost. When we investigated whether App1 would also bind to other complement receptor(s), we found that App1 does bind to complement receptor 2 (CR2) in a dose-dependent manner. In certain lymphoma cell lines, cellular proliferation is stimulated by complement through CR2, providing a potential use of App1 as a proliferation inhibitor of these cells. Initially discovered as an antiphagocytic protein regulating CR3-mediated innate immunity, App1 may also play a key role in the regulation of acquired immunity, because CR2 is mainly localized on B cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ M.D.P. is supported by National Institutes of Health Grants AI56168 and AI71142. C.L. is supported by National Institutes of Health Grant RR17677 Project 6 from the Centers of Biomedical Research Excellence Program of the National Center for Research Resources, and from National Science Foundation/EPSCoR Grant EPS-0132573. M.D.P. is a Burroughs Wellcome New Investigator in Pathogenesis of Infectious Diseases.

² P.S. and V.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Maurizio Del Poeta, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB 503 Charleston, SC 29425. E-mail address: delpoeta{at}musc.edu

⁴ Abbreviations used in this paper: App1, antiphagocytic protein 1; AM, alveolar macrophage; CHO, Chinese hamster ovary; Cn, Cryptococcus neoformans; CR2, complement receptor 2; CR3, complement receptor 3; mPGI, phosphoglucose isomerase from methanosacrina; nApp1, native App1; NEO, neomycin; pAb, polyclonal Ab; PBST, PBS/0.1% Tween 20; WT, wild type.