Bacterial protein-O-mannosylating enzyme is crucial for virulence of Mycobacterium tuberculosis

Chia-Fang Liu1, Laure Tonini, Wladimir Malaga

  • 1Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.

Insights

Protein O-mannosylation is crucial for Mycobacterium tuberculosis (Mtb) virulence. Disrupting this process severely impacts Mtb growth and pathogenicity, highlighting its role in host infection.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Posttranslational Modifications

Background:

  • Protein O-mannosylation, essential in eukaryotes, occurs in Mycobacterium tuberculosis (Mtb) and related actinobacteria.
  • The specific role and prevalence of O-mannosylation in Mtb pathogenesis remain unexplored.

Purpose of the Study:

  • To investigate the biological significance of protein O-mannosylation in Mtb and Mycobacterium smegmatis.
  • To determine the impact of disrupting O-mannosylation on Mtb virulence and growth.

Main Methods:

  • Inactivation of putative protein mannosyl transferase genes (Msmeg_5447 and Rv1002c) in M. smegmatis and Mtb.
  • Mass spectrometry-based glycoproteomics to confirm loss of O-mannosylation.
  • Phenotypic analysis of mutant strains in vitro, in cellulo, and in immunocompromised mice.

Main Results:

  • Loss of protein O-mannosylation was confirmed in both M. smegmatis and Mtb mutant strains.
  • M. smegmatis lacking O-mannosylation showed no significant phenotypic changes.
  • Mtb mutants exhibited severely impaired growth and significantly reduced pathogenicity in vivo.

Conclusions:

  • Protein O-mannosylation is biologically significant in mycobacteria.
  • This posttranslational modification is critical for Mtb virulence and host colonization.

Related Concept Videos

Regulation of Bacterial Virulence01:28

Regulation of Bacterial Virulence

Pathogenic bacteria employ a range of regulatory mechanisms to modulate the expression of virulence genes in response to environmental and host-derived signals. These mechanisms ensure that virulence factors are expressed only under favorable conditions, thereby optimizing infection and survival strategies.Mechanisms of Virulence RegulationKey regulatory strategies include:Two-Component Systems: These consist of a membrane-bound sensor kinase and a cytoplasmic response regulator. Environmental...
Formation of Lipopolysaccharides01:19

Formation of Lipopolysaccharides

Lipopolysaccharides (LPS) are crucial components of the outer membrane of Gram-negative bacteria, serving both structural and functional roles. It contributes to membrane stability and protects bacteria from host immune responses. LPS is composed of three major regions—lipid A, a core oligosaccharide, and an O antigen. The biosynthesis and assembly of LPS involve a highly coordinated set of enzymatic reactions and transport mechanisms. Additionally, LPS is recognized as an endotoxin, triggering...
Bacterial Translocation and Protein Secretion01:26

Bacterial Translocation and Protein Secretion

Bacterial protein secretion involves translocation systems to ensure proteins reach their designated locations, including the plasma membrane, periplasm, outer membrane, or the external environment. These translocation systems are vital for bacterial physiology, supporting processes like membrane assembly, enzymatic activity in the periplasm, and interactions with the external environment. The division of labor between Sec and Tat pathways ensures efficiency in handling proteins with diverse...
Bacterial Meningitis II: Pathophysiology01:26

Bacterial Meningitis II: Pathophysiology

Bacterial meningitis typically begins when pathogens such as Neisseria meningitidis and Streptococcus pneumoniae colonize the nasopharynx and invade the bloodstream. This process is facilitated by bacterial virulence factors, such as polysaccharide capsules, which resist phagocytosis and complement-mediated killing. Less commonly, bacteria reach the central nervous system via contiguous spread from infections like otitis media or sinusitis, through congenital or acquired dural defects, or...
Gram-negative Bacterial Protein Secretion Systems01:17

Gram-negative Bacterial Protein Secretion Systems

Gram-negative bacteria utilize sophisticated protein secretion systems to transport proteins across their double-membrane envelope into the extracellular environment or host cells. Based on their mechanism of action, these systems are classified into one-step and two-step pathways.One-Step Secretion Systems (Types I, III, IV, and VI)One-step secretion systems bypass the periplasm entirely, forming a continuous channel that spans both the inner and outer membranes:Type I Secretion System (T1SS):...
Bacterial Protein Maturation01:26

Bacterial Protein Maturation

Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...