Mycobacterium tuberculosis Uses Mce Proteins to Interfere With Host Cell Signaling

Abstract

Tuberculosis continues to be the main cause for mortality by an infectious agent, making Mycobacterium tuberculosis one of the most successful pathogens to survive for long durations within human cells. In order to survive against host defenses, M. tuberculosis modulates host cell signaling. It employs many proteins to achieve this and the Mce proteins are emerging as one group that play a role in host cell signaling in addition to their primary role as lipid/sterol transporters. Mce proteins belong to the conserved Mce/MlaD superfamily ubiquitous in diderm bacteria and chloroplasts. In mycobacteria, mce operons, encode for six different Mce proteins that assemble with inner membrane permeases into complexes that span across the mycobacterial cell wall. Their involvement in signaling modulation is varied and they have been shown to bind ERK1/2 to alter host cytokine expression; eEF1A1 to promote host cell proliferation and integrins for host cell adherence and entry. Recently, structures of prokaryotic Mce/MlaD proteins have been determined, giving an insight into the conserved domain. In this mini-review, we discuss current evidence for the role of mycobacterial Mce proteins in host cell signaling and structural characteristics of the protein-protein interactions coordinated by the human proteins to modulate the host signaling.

Keywords: EF1A1; ERK; Mce protein; Mycobacterium tuberculosis; host cell signaling; host-pathogen interaction; integrin.

Figure 1

Structures of Mce proteins from E. coli and structures of proteins known to interact with the M. tuberculosis Mce proteins. (A) Mce Transporter: Proposed structure of an Mce Transporter that sits in the mycobacterial membrane interacting with lipids and signaling proteins. (B) MlaD hexamer: The E. coli Mce protein, MlaD, forms a hexamer of the ubiquitous Mce domain (PDB: 5UW2) (Ekiert et al., 2017). (C) Integrin bound RGD Ligand: The propeller of the α subunit and the βA domain of the ß subunit binds the RGD motif of its ligand to initiate intracellular signaling (Xiong et al., 2002) (PDB: 1L5G). (D) LetB: An E. coli protein with seven tandem Mce domains that forms a hexamer that spans the periplasm (Isom et al., 2019) (PDB available from http://bhabhaekiertlab.org/pdb-links). (E) ERK2 bound PEA-15: PEA-15 binds ERK2 in a bipartite manner to inhibit it (Mace et al., 2013) (PDB: 4IZ5). (F) eEF1A1: The elongation factor alpha 1 has three distinct domains, I, II, III (Andersen et al., 2000) (PDB: 1F60).

Figure 2

M. tuberculosis Mce proteins are involved in modulating host cell signaling. (A) Domains and motifs of Mce proteins: Each M. tuberculosis Mce (1–4) Transporter is composed of six Mce proteins (A–F). Twenty-one have transmembrane domains (TM) and the remaining three (1E, 3E, 4E) contain lipoprotein attachment sites. Each protein has a conserved Mce domain with unique C-terminal domains including the Cholesterol uptake porter (CUP) domain (1A, 1D, 2A, 2F, 3A, 4A, 4D); RGD motifs for probable integrin binding (1D, 1E, 2D, 2E, 3A, 3C, 4D, 4E); DEF motifs (2D, 3E, 4E). (B) Mce proteins interact with host cell signaling proteins. Epithelial cell: Mce2E of M. tuberculosis binds to domain I of eEF1A1 preventing its K-48 linked ubiquitination and preventing its proteasomal degradation leading to epithelial cell proliferation. Macrophage cell: Mce3C from M. tuberculosis binds ß2 integrin on macrophage surfaces thereby co-ordinating actin rearrangements to enable its cell entry. Mce3C binds ß2 integrin via an RGD motif interaction with DxSxS motif on the integrin. Once intracellular, Mce2E and Mce3E bind to ERK1/2 preventing its phosphorylation by MEK1/2 and its nuclear translocation leading to suppression of the activation of the ERK signaling pathway. Inset: Mce3E binds using a D- domain motif binding to a site away from the activation loop of ERK. Mce2E binds using a DEF-motif, FPFP, binding to the DEF binding site located at the activation loop of ERK.