Abstract
Multiple regulatory mechanisms including post-translational modifications (PTMs) confer complexity to the simpler genomes and proteomes of Mycobacterium tuberculosis (Mtb). PTMs such as glycosylation play a significant role in Mtb adaptive processes. The glycoproteomic patterns of clinical isolates of the Mycobacterium tuberculosis complex (MTBC) representing the lineages 3, 4, 5 and 7 were characterized by mass spectrometry. A total of 2944 glycosylation events were discovered in 1325 proteins. This data set represents the highest number of glycosylated proteins identified in Mtb to date. O-glycosylation constituted 83% of the events identified, while 17% of the sites were N-glycosylated. This is the first report on N-linked protein glycosylation in Mtb and in Gram-positive bacteria. Collectively, the bulk of Mtb glycoproteins are involved in cell envelope biosynthesis, fatty acid and lipid metabolism, two-component systems, and pathogen-host interaction that are either surface exposed or located in the cell wall. Quantitative glycoproteomic analysis revealed that 101 sites on 67 proteins involved in Mtb fitness and survival were differentially glycosylated between the four lineages, among which 64% were cell envelope and membrane proteins. The differential glycosylation pattern may contribute to phenotypic variabilities across Mtb lineages. The study identified several clinically important membrane-associated glycolipoproteins that are relevant for diagnostics as well as for drug and vaccine discovery.
Highlights
Tuberculosis (TB) is a major threat to public health, causing more than three deaths per minute globally
The cell wall core is composed of peptidoglycan (PG) covalently linked via phosphoryl-N-acetylglucosaminosylrhamnosyl to arabinogalactan (AG), which in turn is esterified to α-alkyl, β-hydroxy long-chain mycolic acids, forming the mycolyl arabinogalactan-peptidoglycan complex[1,15]
The data was further filtered using localization probability of 0.7, PEP of 0.05 and having valid values in at least one sample resulted in 2944 class-I glycosylation events derived from 1325 unique proteins in Mycobacterium tuberculosis complex (MTBC) strains representing lineages 3, 4, 5 and 7
Summary
Tuberculosis (TB) is a major threat to public health, causing more than three deaths per minute globally. The cell wall core is composed of peptidoglycan (PG) covalently linked via phosphoryl-N-acetylglucosaminosylrhamnosyl to arabinogalactan (AG), which in turn is esterified to α-alkyl, β-hydroxy long-chain mycolic acids, forming the mycolyl arabinogalactan-peptidoglycan (mAGP) complex[1,15]. This complex is essential for bacterial viability and is the basis of susceptibility and resistance to many anti-TB drugs including ethambutol (EMB) and ethionamide (ETH)[12,16]. In Mtb, MurNGly, MurNAc and Mur residues are present in the precursor pool and in the PG20
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