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Structure of an endogenous mycobacterial MCE lipid transporter

ABSTRACT: Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the leading causes of death due to infectious disease. The Mammalian Cell Entry proteins are essential virulence factors during infection and are thought to facilitate the import of nutrients across the highly complex mycobacterial cell envelope. We purified an endogenous Mammalian Cell Entry complex from the model mycobacterium, Mycobacterium smegmatis, identified components of the Mce1 protein complex using mass spectrometry, and determined its structure using single-particle cryo-electron microscopy and AlphaFold2. This entry contains the mass spectrometry raw files and search results for the LC-MS analysis of the purified complex.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mycobacterium Smegmatis Str. Mc2 155 (ncbitaxon:246196)

SUBMITTER: Beatrix Ueberheide

PROVIDER: MSV000090807 | MassIVE | Tue Nov 29 13:12:00 GMT 2022

SECONDARY ACCESSION(S): PXD038456

REPOSITORIES: MassIVE

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Project description:Phagocytosis requires the activation of a plethora of mechanisms that include the activation of the actin cytoskeleton guided by the Arp2/3 complex. These are promoted by activators such as the Wiskott Aldrich Syndrome Protein (WASP) family members. In order to further understand the molecular mechanisms involved in the early events leading the phagocytosis of the pathogenic Mycobacterium tuberculosis, we set out to examine potential roles of miRNAs in phagocytosis using genome-wide expression profiling to identify miRNAs differentially regulated following mycobacterial infection. One of the miRNAs activated upon infection of mouse macrophages with the non-pathogenic Mycobacterium smegmatis, the widely conserved miR-142-3p, was predicted and confirmed to target the Neural-WASP (N-WASP). Upregulating of miR-142-3p in mouse macrophages inversely correlated with levels of N-WASP, upon infection with live pathogenic and non-pathogenic mycobacteria, suggesting an active role of Mycobacterium tuberculosis on the regulation of phagocytosis, at the post-transcriptional level, in host cells. The reduction of N-WASP correlated with a reduced internalization of bacteria per macrophage, independently of the phagocytosis index. Furthermore, the downregulation of WASP levels accompanied those of N-WASP, at early but not at late time points, suggesting a closely regulatory mechanism among both family members, dependent on the time frame of the phagocytosis. Additionally, upregulating of miR-142-3p promoted the change in the protein levels of another predicted and confirmed target, the Cofilin2 protein, in a phagocytosis-independent fashion. Downregulation experiments promoted aberrant morphologic phenotypes in macrophages, similar to observed by others in PBMCs of humans with Wiskott Aldrich Syndrome, suggesting the strong involvement of miR-142-3p on the regulation of the actin machinery in macrophages. Altogether these results show for the first time that miRNAs are involved in the regulation of actin-mediated phagocytosis of pathogenic bacteria and that these are direct targets of Mycobacterium tuberculosis. Expression analysis of mouse macrophage cell line J774A.1 in response to infection with Mycobacterium smegmatis mc2155 EGFP. Three biological replicates each for uninfected and infected samples.

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Structure of an endogenous mycobacterial MCE lipid transporter

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