A new role for lipoproteins LpqZ and FecB in orchestrating mycobacterial cell envelope biogenesis
Bibliographic record
Abstract
ABSTRACT Accounting for more deaths than any other bacterial species, Mycobacterium tuberculosis (Mtb) represents a critical threat to public health worldwide. A key factor contributing to Mtb’s virulence is its unique cell envelope, which acts as a protective barrier. Among the components of this envelope, lipoproteins represent a critical but understudied group of proteins. In this study, we focused on 79 conserved putative lipoproteins, shared between Mtb and the closely related M. marinum . Leveraging the CRISPR/Cas9 gene editing system for Mycobacteria, we generated frameshift mutations, targeting one conserved lipoprotein-coding gene at a time. We identified two mutants, lpqZ and fecB , that exhibited increased susceptibility to all tested antibiotics, suggesting critical roles in cell envelope biogenesis. Interestingly, despite having homology to periplasmic substrate-binding proteins (SBPs), neither protein is associated with any inner membrane transporter complex. Instead, co-immunoprecipitation experiments revealed that LpqZ interacts with AftA and FecB interacts with AftB. Both these interaction partners are essential enzymes involved in arabinogalactan and lipoarabinomannan synthesis. Accordingly, we observed alterations for both glycoconjugates in lpqZ and fecB mutants. Together, these findings show that orphaned SBP-like proteins have been repurposed in mycobacteria to aid key enzymes involved in cell envelope biosynthesis. IMPORTANCE Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains the world’s deadliest bacterial infection, in part because the bacterium’s unique cell envelope makes it highly resistant to antibiotics. Understanding how this protective barrier is built is essential for developing better treatments. In this study, we discovered that two previously uncharacterized lipoproteins help maintain the integrity of the mycobacterial cell envelope and contribute to drug resistance. Surprisingly, instead of acting as transport proteins as expected by structural similarity, these molecules regulate enzymes that assemble the bacterial envelope. This discovery highlights a previously unrecognized layer of control in envelope construction and opens new directions for targeting Mtb’s defenses with future therapies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".