Delineating the Physiological Roles of the PE and Catalytic Domains of LipY in Lipid Consumption in Mycobacterium-Infected Foamy Macrophages

Santucci, Pierre; Diomande, Sadia; Poncin, Isabelle; Alibaud, Laetitia; Viljoen, Albertus; Kremer, Laurent; Chastellier, Chantal de; Canaan, Stéphane

doi:10.1128/iai.00394-18

Cited by 26 publications

(47 citation statements)

References 61 publications

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“…In addition, the 21 first amino acid residues of the linker region in LipY∆149 (Fig. D–E) seem to be essential for the enzyme activity, possibly by stabilizing this extracellular mature form in a suitable conformation within the cell wall and during TAG hydrolysis, as previously proposed .…”

Section: Resultssupporting

confidence: 66%

“…To gain further insight into this molecular mechanism, 3D structural models were generated using the I-TASSER server. As proposed previously [14,54], the Nterminal PE domain could be easily distinguished from the C-terminal domain and is composed of four a-helices (a1 to a4) ( Fig. 2B highlighted in blue) [14,54].…”

Section: Overexpression Of Lipy Variants Increased Tag Consumption Insupporting

confidence: 67%

“…As proposed previously [14,54], the Nterminal PE domain could be easily distinguished from the C-terminal domain and is composed of four a-helices (a1 to a4) ( Fig. 2B highlighted in blue) [14,54]. Comparison of the LipY and LipYDPE models [14] suggests that the four a-helices of the PE domain cover the active site of the enzyme.…”

Section: Overexpression Of Lipy Variants Increased Tag Consumption Insupporting

confidence: 59%

“…In Mycobacterium marinum LipY, the PE domain is substituted by a PPE domain [28] and the presence of this surface-exposed mature LipY strongly increases its TAG hydrolase activity [25]. Recently, we have demonstrated that a Mycobacterium bovis BCG DlipY mutant is impaired in ILI formation within foamy macrophages, suggesting that LipY is an essential factor involved in host-derived TAG consumption [14]. Additional biochemical data indicated that LipY lacking its PE domain expresses increased TAG-hydrolase activity in vitro [28], suggesting that the PE domain acts as a modulator of the catalytic activity [14,28].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have demonstrated that a Mycobacterium bovis BCG DlipY mutant is impaired in ILI formation within foamy macrophages, suggesting that LipY is an essential factor involved in host-derived TAG consumption [14]. Additional biochemical data indicated that LipY lacking its PE domain expresses increased TAG-hydrolase activity in vitro [28], suggesting that the PE domain acts as a modulator of the catalytic activity [14,28]. Collectively, these findings imply that LipY plays a central role in TAG metabolism during the Mtb life cycle by participating in the hydrolytic processes of both extracellular and intracellular lipids.…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the membrane lipid binding properties and lipase activity of Mycobacterium tuberculosis LipY domains

et al. 2019

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The Mycobacterium tuberculosis LipY protein, a prototype of the proline‐glutamic acid (PE) family, exhibits a triacylglycerol (TAG) hydrolase activity that contributes to host cell lipid degradation and persistence of the bacilli. LipY is found either as a full‐length intracytosolic form or as a mature extracellular form lacking the N‐terminal PE domain. Even though the contribution of the extracellular form in TAG consumption has been partly elucidated, very little information is available regarding the potential interactions of either full‐length LipY with the cytoplasmic membrane, or mature form LipY with the outer membrane. Herein, several LipY variants truncated in their N‐terminal domain were produced and biochemically characterized in lipid–protein interaction assays, using the monomolecular film technique and FTIR. Comparison of the catalytic activities of these recombinant proteins showed that LipY∆149, corresponding to the extracellular form of LipY lacking the PE domain, is more active than the full‐length protein. This confirms previous studies reporting that the PE domain negatively modulates the TAG hydrolase activity of LipY. Lipid–protein interaction studies indicate that the PE domain anchors LipY onto membrane lipids. Consistent with these findings, we show that LipY∆149 is loosely associated with the mycobacterial cell wall, and that this interaction is mediated by the sole lipase domain. Overall, our results bring new information regarding the molecular mechanisms by which LipY either binds and hydrolyses host cell lipids or degrades TAG, the major source of lipids within mycobacterial intracytosolic lipid inclusions.

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Section: Resultssupporting

confidence: 66%

Section: Overexpression Of Lipy Variants Increased Tag Consumption Insupporting

confidence: 67%

Section: Overexpression Of Lipy Variants Increased Tag Consumption Insupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dissecting the membrane lipid binding properties and lipase activity of Mycobacterium tuberculosis LipY domains

et al. 2019

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Intrabacterial lipid inclusion‐associated proteins: a core machinery conserved from saprophyte Actinobacteria to the human pathogen Mycobacterium tuberculosis

Dargham,

Mallick,

Kremer

et al. 2023

FEBS Open Bio

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Mycobacterium tuberculosis (Mtb), the aetiologic agent of tuberculosis (TB), stores triacylglycerol (TAG) in the form of intrabacterial lipid inclusions (ILI) to survive and chronically persist within its host. These highly energetic molecules represent a major source of carbon to support bacterial persistence and reactivation, thus playing a leading role in TB pathogenesis. However, despite its physiological and clinical relevance, ILI metabolism in Mtb remains poorly understood. Recent discoveries have suggested that several ILI‐associated proteins might be widely conserved across TAG‐producing prokaryotes, but still very little is known regarding the nature and the biological functions of these proteins. Herein, we performed an in silico analysis of three independent ILI‐associated proteomes previously reported to computationally define a potential core ILI‐associated proteome, referred to as ILIome. Our investigation revealed the presence of 70 orthologous proteins that were strictly conserved, thereby defining a minimal ILIome core. We further narrowed our analysis to proteins involved in lipid metabolism and discuss here their putative biological functions, along with their molecular interactions and dynamics at the surface of these bacterial organelles. We also highlight the experimental limitations of the original proteomic investigations and of the present bioinformatic analysis, while describing new technological approaches and presenting biological perspectives in the field. The in silico investigation presented here aims at providing useful datasets that could constitute a scientific resource of broad interest for the mycobacterial community, with the ultimate goal of enlightening ILI metabolism in prokaryotes with a special emphasis on Mtb pathogenesis.

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Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

et al. 2019

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In the quest for new antibacterial agents, a series of novel long‐ and medium‐chain mono‐ and disubstituted β‐lactones was developed. Their activity against three pathogenic mycobacteria—M. abscessus, M. marinum, and M. tuberculosis—was assessed by the resazurin microtiter assay (REMA). Among the 16 β‐lactones synthesized, only 3‐hexadecyloxetan‐2‐one (VM005) exhibited promising activity against M. abscessus, whereas most of the β‐lactones showed interesting activities against M. marinum, similar to that of the classical antibiotic, isoniazid. Regarding M. tuberculosis, six compounds were found to be active against this mycobacterium, with β‐lactone VM008 [trans‐(Z)‐3‐(hexadec‐7‐en‐1‐yl)‐4‐propyloxetan‐2‐one] being the best growth inhibitor. The promising antibacterial activities of the best compounds in this series suggest that these molecules may serve as leads for the development of much more efficient antimycobacterial agents.

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Delineating the Physiological Roles of the PE and Catalytic Domains of LipY in Lipid Consumption in Mycobacterium-Infected Foamy Macrophages

Cited by 26 publications

References 61 publications

Dissecting the membrane lipid binding properties and lipase activity of Mycobacterium tuberculosis LipY domains

Dissecting the membrane lipid binding properties and lipase activity of Mycobacterium tuberculosis LipY domains

Intrabacterial lipid inclusion‐associated proteins: a core machinery conserved from saprophyte Actinobacteria to the human pathogen Mycobacterium tuberculosis

Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

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