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Talaromyces marneffei Mp1 protein, a novel virulence factor, carries two arachidonic acid-binding domains to suppress inflammatory responses in hosts

DOI: 10.1128/IAI.00679-18 DOI Help

Authors: Wai-hei Lam (The University of Hong Kong) , Kong-hung Sze (The University of Hong Kong) , Yihong Ke (The University of Hong Kong) , Man-kit Tse (The University of Hong Kong) , Hongmin Zhang (The University of Hong Kong; Southern University of Science and Technology, China) , Patrick C. Y. Woo (The University of Hong Kong) , Susanna K. P. Lau (The University of Hong Kong) , Candy C. Y. Lau (The University of Hong Kong) , Simin Xu (The University of Hong Kong) , Pok-man Lai (The University of Hong Kong) , Ting Zhou (The University of Hong Kong) , Svetlana A. Antonyuk (University of Liverpool) , Richard Y. T. Kao (The University of Hong Kong) , Kwok-yung Yuen (The University of Hong Kong) , Quan Hao (The University of Hong Kong)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Infection And Immunity

State: Published (Approved)
Published: January 2019

Abstract: Talaromyces marneffei (T. marneffei) infection causes talaromycosis (previously known as penicilliosis), the second most-deadly opportunistic systematic mycosis in immuno-compromised patients. Different virulence mechanisms in T. marneffei had been proposed and investigated. In the sera of patients with talaromycosis, Mp1 protein (Mp1p), a secretory galactomannoprotein antigen encoding two tandem ligand-binding domains (Mp1p-LBD1 and Mp1p-LBD2), was found to be abundant. Mp1p-LBD2 was reported to possess a hydrophobic cavity to bind co-purified palmitic acid (PLM). It was hypothesized that capturing of lipids from human hosts by expressing large quantity of Mp1p may be a possible virulence mechanism of T. marneffei. It was shown that expression of Mp1p enhanced the intracellular survival of T. marneffei by suppressing pro-inflammatory responses. Mechanistic study of Mp1p-LBD2 suggested that arachidonic acid (AA), precursor of paracrine signaling molecules for regulations of inflammatory responses, is the major physiological target of Mp1p-LBD2. In this study, we use crystallographic and biochemical techniques to further demonstrate that Mp1p-LBD1, the previously unsolved first lipid binding domain of Mp1p, is also a strong AA-binding domain in Mp1p. These studies on Mp1p-LBD1 support that the highly-expressed Mp1p is an effective AA-capturing protein. Each Mp1p can bind up to 4 AA molecules. The crystal structure of Mp1p-LBD1-LBD2 has also been solved, showing that both LBDs are likely to function independently with a flexible linker in between. T. marneffei and potentially other pathogens highly expressing and secreting proteins similar to Mp1p can severely disturb hosts' signaling cascades during pro-inflammatory responses, by reducing the availabilities of important paracrine signaling molecules.

Journal Keywords: virulence factor; X-ray crystallography; lipid-protein interaction; NMR; 27 arachidonic acid (AA)

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography

Other Facilities: SOLEIL; NSRRC; SSRF