Toward Understanding the Essence of Post-Translational Modifications for the Mycobacterium tuberculosis Immunoproteome

Abstract

CD4(+) T cells are prominent effector cells in controlling Mycobacterium tuberculosis (Mtb) infection but may also contribute to immunopathology. Studies probing the CD4(+) T cell response from individuals latently infected with Mtb or patients with active tuberculosis using either small or proteome-wide antigen screens so far revealed a multi-antigenic, yet mostly invariable repertoire of immunogenic Mtb proteins. Recent developments in mass spectrometry-based proteomics have highlighted the occurrence of numerous types of post-translational modifications (PTMs) in proteomes of prokaryotes, including Mtb. The well-known PTMs in Mtb are glycosylation, lipidation, or phosphorylation, known regulators of protein function or compartmentalization. Other PTMs include methylation, acetylation, and pupylation, involved in protein stability. While all PTMs add variability to the Mtb proteome, relatively little is understood about their role in the anti-Mtb immune responses. Here, we review Mtb protein PTMs and methods to assess their role in protective immunity against Mtb.

Keywords: CD4+ T cell epitope; MHC ligands; Mycobacterium tuberculosis; T cell epitope repertoire; immunoproteome; post-translational modification; proteomics.

Figure 1

Molecular and immunological hallmarks of naturally methylated HBHA. (A) LC-MS analysis (lower part) and summary of methylation pattern (upper part) of HBHA from BCG. Indicated by arrows are the masses of molecular variants in the mass envelope, the lowest and highest of which correspond to HBHA containing 0 or 25 methyl groups, respectively. Methylations are borne by the lysine residues of the C-terminal part. Data indicate that at least 13 out of the 16 C-terminal lysines can be mono- or dimethylated. (B) In vitro IFNγ release to methylated HBHA stimulation according to Mtb infection status. Shown are IFNγ concentrations in nanogram/milliter as measured in Elisa after stimulation with methylated HBHA for 24 h of PBMC from three groups of subjects: non-infected controls (CTRL), subjects with latent Mtb infection (LTBI), and patients with active tuberculosis (TB). The dotted line represents the positivity cut-off for the assay. For each group, the median of results is marked as a horizontal line. Statistical significance of differences: ***p ≤ 0.0001. Data are with licensed permission from Ref. (23).