Autophagy-Related Proteins Target Ubiquitin-Free Mycobacterial Compartment to Promote Killing in Macrophages

Bah, Aïcha; Lacarrière, Camille; Vergne, Isabelle

doi:10.3389/fcimb.2016.00053

Cited by 13 publications

(17 citation statements)

References 68 publications

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“…The phagosome–cytosol interplay may substantially impact on apoptosis and autophagy in the infected host phagocytes [49], both these cellular responses being efficient in controlling the intracellular growth of the RGM, M. smegmatis and M. fortuitum [24,50,51]. Here, we evaluated the extent of apoptosis following infection of THP-1 Mϕ with M. abscessus S, following annexin-V labelling.…”

Section: Resultsmentioning

confidence: 99%

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

et al. 2016

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Mycobacterium abscessus is a pathogenic, rapidly growing mycobacterium responsible for pulmonary and cutaneous infections in immunocompetent patients and in patients with Mendelian disorders, such as cystic fibrosis (CF). Mycobacterium abscessus is known to transition from a smooth (S) morphotype with cell surface-associated glycopeptidolipids (GPL) to a rough (R) morphotype lacking GPL. Herein, we show that M. abscessus S and R variants are able to grow inside macrophages and are present in morphologically distinct phagosomes. The S forms are found mostly as single bacteria within phagosomes characterized by a tightly apposed phagosomal membrane and the presence of an electron translucent zone (ETZ) surrounding the bacilli. By contrast, infection with the R form leads to phagosomes often containing more than two bacilli, surrounded by a loose phagosomal membrane and lacking the ETZ. In contrast to the R variant, the S variant is capable of restricting intraphagosomal acidification and induces less apoptosis and autophagy. Importantly, the membrane of phagosomes enclosing the S forms showed signs of alteration, such as breaks or partial degradation. Although not frequently encountered, these events suggest that the S form is capable of provoking phagosome–cytosol communication. In conclusion, M. abscessus S exhibits traits inside macrophages that are reminiscent of slow-growing mycobacterial species.

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Section: Resultsmentioning

confidence: 99%

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

et al. 2016

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“…The TLR/MyD88 signaling pathway is known to promote autophagy [3], in particular in mycobacteria-infected macrophages [22,37]. Therefore, we investigated its role in PMM127-induced autophagy.…”

Section: The Mtb Mutant Deficient In Dims and Sls Promoted Autophagy mentioning

confidence: 99%

“…TLR2, one of the main PRRs (pattern recognition receptors) that recognize Mtb [40], has been implicated in autophagy activation in the context of mycobacterial infection [22,41,42]. Next, we investigated whether SLs and DIMs could per se limit TLR2-dependent autophagy by testing purified SL and DIM molecules.…”

Section: Synthetic Sl But Not Purified Dim Molecules Limited Tlr2-dmentioning

confidence: 99%

“…The autophagy machinery of Beclin-1, Atg16L1, and LC3 targeted Mtb mutants deficient in DIMs and SLs (Figures 1 and 2). To determine whether the Mtb-containing compartments positive for LC3 could be acidified, infected macrophages were stained with LysoTracker Red (LTR) and analyzed using immunofluorescence confocal microscopy [22]. At 72 h p.i., while only 30% of WT Mtb within the LC3-positive compartments was colocalized with LTR, we observed that more than 50% of the LC3-positive compartments containing PMM127 were acidified ( Figure 6A,B), indicating that PMM127 not only enhanced LC3 recruitment compared to the WT (Figure 1) but also increased the acidification of LC3-positive bacterial compartments.…”

Section: Dims But Not Sls Limited the Acidification Of Lc3-positivementioning

confidence: 99%

“…Some of them are potent immunomodulators. They can act as ligands of toll-like receptor 2 (TLR2) and can trigger autophagy upon phagocytosis [22,23]. Others, such as mannose-capped lipoarabinomannan, limit LC3 recruitment onto latex beads containing phagosomes via an unknown mechanism [23,24].…”

Section: Introductionmentioning

confidence: 99%

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The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Bah

Sanicas

Nigou

et al. 2020

Cells

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Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.

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The Antioxidant Properties of Bioactive Peptides Derived from Enzymatic Hydrolyzed or Fermented Canola Meal and Its Effects on Broiler Chickens

Hosseinpoor

Navidshad

Jahromi³

et al. 2023

Int J Pept Res Ther

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Autophagy-Related Proteins Target Ubiquitin-Free Mycobacterial Compartment to Promote Killing in Macrophages

Cited by 13 publications

References 68 publications

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

The Antioxidant Properties of Bioactive Peptides Derived from Enzymatic Hydrolyzed or Fermented Canola Meal and Its Effects on Broiler Chickens

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