Abstract
The bacterial human pathogen Chlamydia trachomatis invades cells as an infectious elementary body (EB). The EB is internalized into a vacuole that is hidden from the host defense mechanism, and is modified to sustain the development of the replicative reticulate body (RB). Inside this parasitophorous compartment, called the inclusion, the pathogen survives supported by an active exchange of nutrients and proteins with the host cell. We show that host lipids are scavenged and modified into bacterial-specific lipids by the action of a shared human-bacterial acylation mechanism. The bacterial acylating enzymes for the essential lipids 1-acyl-sn-glycerol 3-phosphate and 1-acyl-sn-phosphatidylcholine were identified as CT453 and CT775, respectively. Bacterial CT775 was found to be associated with lipid droplets (LDs). During the development of C. trachomatis, the human acyl-CoA carrier hACBD6 was recruited to cytosolic LDs and translocated into the inclusion. hACBD6 protein modulated the activity of CT775 in an acyl-CoA dependent fashion and sustained the activity of the bacterial acyltransferase by buffering the concentration of acyl-CoAs. We propose that disruption of the binding activity of the acyl-CoA carrier might represent a new drug-target to prevent growth of C. trachomatis.
Highlights
Integrity of eukaryotic membranes is maintained by processes that require the continuous renewal of lipid molecules
We show that a member of the human acyl-co-enzyme A (CoA) binding protein family, hACBD6 (Soupene et al 2008b), which is not associated with lipid droplets (LDs) in un-infected cells, binds to LDs during development of C. trachomatis and expansion of the inclusion; hACBD6 was exhaustively removed from the nucleus of the infected host cells and was translocated into the lumen of the inclusion apparently in association with LDs
A recombinant GST-CT453 protein was insoluble but it was active in vivo and could rescue the growth defect of an E. coli plsCts mutant lacking lysophosphatidic acid acyl transferase (LPAAT) activity at 37°C (Figs. 1B and S1A)
Summary
Integrity of eukaryotic membranes is maintained by processes that require the continuous renewal of lipid molecules. The re-acylation of the resulting lysophospholipid (lysoPL) is achieved by a co-enzyme A (CoA) and ATP-dependent two-step process (Lands 1960). Fatty acids are activated to acyl-CoAs by membrane-bound long-chain acyl-CoA synthetases (ACSL) and are transferred to the lysoPL acceptor by membrane-bound acyl-CoA:Lysophospholipid-acyltransferases (LPLAT) (Lands 1960; Lands and Merkl 1963; Merkl and Lands 1963; Lands and Hart 1965). The combined de-acylation, activation and re-acylation represents the Lands’ pathway supporting lipid repair and remodeling of membranes, as well as the removal of bio-active and pro-inflammatory lysoPL molecules (Lands 1960)
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