The mycobacterial glycoside hydrolase LamH enables capsular arabinomannan release and stimulates growth

Aaron Franklin, Vivian C. Salgueiro, Abigail J. Layton, Rudi Sullivan, Todd Mize, Lucía Vázquez-Iniesta, Samuel T. Benedict, Sudagar S. Gurcha, Itxaso Anso, Gurdyal S. Besra, Manuel Banzhaf, Andrew L. Lovering, Spencer J. Williams, Marcelo E. Guerin, Nichollas E. Scott, Rafael Prados-Rosales, Elisabeth C. Lowe () and Patrick J. Moynihan ()
Additional contact information
Aaron Franklin: University of Birmingham
Vivian C. Salgueiro: Public Health and Microbiology, School of Medicine, Universidad Autonoma de Madrid
Abigail J. Layton: University of Birmingham
Rudi Sullivan: University of Birmingham
Todd Mize: University of Birmingham
Lucía Vázquez-Iniesta: Public Health and Microbiology, School of Medicine, Universidad Autonoma de Madrid
Samuel T. Benedict: University of Birmingham
Sudagar S. Gurcha: University of Birmingham
Itxaso Anso: Spanish National Research Council
Gurdyal S. Besra: University of Birmingham
Manuel Banzhaf: University of Birmingham
Andrew L. Lovering: University of Birmingham
Spencer J. Williams: University of Melbourne
Marcelo E. Guerin: Spanish National Research Council (CSIC)
Nichollas E. Scott: University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Rafael Prados-Rosales: Public Health and Microbiology, School of Medicine, Universidad Autonoma de Madrid
Elisabeth C. Lowe: Newcastle University
Patrick J. Moynihan: University of Birmingham

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Mycobacterial glycolipids are important cell envelope structures that drive host-pathogen interactions. Arguably, the most important are lipoarabinomannan (LAM) and its precursor, lipomannan (LM), which are trafficked from the bacterium to the host via unknown mechanisms. Arabinomannan is thought to be a capsular derivative of these molecules, lacking a lipid anchor. However, the mechanism by which this material is generated has yet to be elucidated. Here, we describe the identification of a glycoside hydrolase family 76 enzyme that we term LamH (Rv0365c in Mycobacterium tuberculosis) which specifically cleaves α−1,6-mannoside linkages within LM and LAM, driving its export to the capsule releasing its phosphatidyl-myo-inositol mannoside lipid anchor. Unexpectedly, we found that the catalytic activity of this enzyme is important for efficient exit from stationary phase cultures, potentially implicating arabinomannan as a signal for growth phase transition. Finally, we demonstrate that LamH is important for M. tuberculosis survival in macrophages.

Date: 2024
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DOI: 10.1038/s41467-024-50051-3

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