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J. Biol. Chem., Vol. 279, Issue 22, 22973-22982, May 28, 2004

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Tsukamurella paurometabola Lipoglycan, a New Lipoarabinomannan Variant with Pro-inflammatory Activity^*

Kevin J. C. Gibson, Martine Gilleron, Patricia Constant, Thérèse Brando, Germain Puzo, Gurdyal S. Besra¶, and Jérôme Nigou

From the School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom and the Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale, CNRS, Unité Mixte de Recherche 5089, 205 Route de Narbonne, 31077 Toulouse, cedex 4, France

The genus Tsukamurella is a member of the phylogenetic group nocardioform actinomycetes and is closely related to the genus Mycobacterium. The mycobacterial cell envelope contains lipoglycans, and of particular interest is lipoarabinomannan, one of the most potent mycobacterial immunomodulatory molecules. We have investigated the presence of lipoglycans in Tsukamurella paurometabola and report here the isolation and structural characterization of a new lipoarabinomannan variant, designated TpaLAM. Matrix-assisted laser desorption ionization-mass spectrometric analysis revealed that TpaLAM had an average molecular mass of 12.5 kDa and consequently was slightly smaller than Mycobacterium tuberculosis lipoarabinomannan. Using a range of chemical degradations, NMR experiments, capillary electrophoresis, and mass spectrometry analyses, TpaLAM revealed an original carbohydrate structure. Indeed, TpaLAM contained a mannosylphosphatidyl-myo-inositol (MPI) anchor glycosylated by a linear (16)-Manp mannan domain, which is further substituted by an (15)-Araf chain. Half of the Araf units are further substituted at the O-2 position by a Manp-(12)-Manp-(1 dimannoside motif. Altogether, TpaLAM appears to be the most elaborated non-mycobacterial LAM molecule identified to date. TpaLAM was found to induce the pro-inflammatory cytokine tumor necrosis factor (TNF)- when tested with either human or murine monocyte/macrophage cell lines. This induction was completely abrogated in the presence of an anti-toll-like receptor-2 (TLR-2) antibody, suggesting that TLR-2 participates in the mediation of TNF- production in response to TpaLAM. Moreover, we established that the lipomannan core of TpaLAM is the primary moiety responsible for the observed TNF--inducing activity. This conclusively demonstrates that a linear (16)-Manp chain, linked to the MPI anchor, is sufficient in providing pro-inflammatory activity.

Received for publication, October 3, 2003 , and in revised form, February 24, 2004.

^* This work was supported in part by grants from the CNRS (France) (to G. P.). 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.

^¶ A Lister Institute-Jenner Research Fellow and supported by grants from the Medical Research Council (UK) (G9901077 and G9901078) and the Wellcome Trust (058972). To whom correspondence should be addressed. Tel.: 0121-415-8125; Fax: 0121-414-5925; E-mail: g.besra{at}bham.ac.uk.

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