ArfGAP1 restricts Mycobacterium tuberculosis entry by controlling the actin cytoskeleton

• Published in: EMBO reports Vol. 19; no. 1; pp. 29 - 42
• Main Authors: Song, Ok‐Ryul, Queval, Christophe J, Iantomasi, Raffaella, Delorme, Vincent, Marion, Sabrina, Veyron‐Churlet, Romain, Werkmeister, Elisabeth, Popoff, Michka, Ricard, Isabelle, Jouny, Samuel, Deboosere, Nathalie, Lafont, Frank, Baulard, Alain, Yeramian, Edouard, Marsollier, Laurent, Hoffmann, Eik, Brodin, Priscille
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2018; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: A549 Cells; Acetylcholine receptors (muscarinic); Actin; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - microbiology; Actin Cytoskeleton - ultrastructure; Actins - genetics; Actins - metabolism; Adenosine diphosphate; ADP-ribosylation; ADP-ribosylation factor 1; ADP-Ribosylation Factor 1 - genetics; ADP-Ribosylation Factor 1 - metabolism; Arf1; ArfGAP1; Cancer; Colonization; Cortex; Cytoskeleton; EMBO05; EMBO23; epithelial cell; Epithelial cells; Gene Expression Regulation; GTPase-activating protein; GTPase-Activating Proteins - antagonists & inhibitors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; Host-Pathogen Interactions; Humans; Life Sciences; Molecular modelling; Mycobacterium tuberculosis; Mycobacterium tuberculosis - pathogenicity; Mycobacterium tuberculosis - physiology; Pathogens; Phospholipase; Phospholipase D - genetics; Phospholipase D - metabolism; Phospholipase D1; Polymerization; Pseudotuberculosis; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - microbiology; Receptor, Muscarinic M3 - genetics; Receptor, Muscarinic M3 - metabolism; Ribosylation; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Scientific Report; Scientific Reports; Shigella flexneri - physiology; Signal Transduction; Species Specificity; Tuberculosis; Yersinia pseudotuberculosis - physiology; phospholipase D1; Arf1; ArfGAP1; epithelial cell; Mycobacterium tuberculosis; phospho- lipase D1 Subject Categories Cell Adhesion; Virology & Host Pathogen Interaction; Microbiology; Polarity & Cytoskeleton
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201744371

The interaction of Mycobacterium tuberculosis (Mtb) with pulmonary epithelial cells is critical for early stages of bacillus colonization and during the progression of tuberculosis. Entry of Mtb into epithelial cells has been shown to depend on F‐actin polymerization, though the molecular mechanisms are still unclear. Here, we demonstrate that mycobacterial uptake into epithelial cells requires rearrangements of the actin cytoskeleton, which are regulated by ADP‐ribosylation factor 1 (Arf1) and phospholipase D1 (PLD1), and is dependent on the M3 muscarinic receptor (M 3 R). We show that this pathway is controlled by Arf GTPase‐activating protein 1 (ArfGAP1), as its silencing has an impact on actin cytoskeleton reorganization leading to uncontrolled uptake and replication of Mtb. Furthermore, we provide evidence that this pathway is critical for mycobacterial entry, while the cellular infection with other pathogens, such as Shigella flexneri and Yersinia pseudotuberculosis , is not affected. Altogether, these results reveal how cortical actin plays the role of a barrier to prevent mycobacterial entry into epithelial cells and indicate a novel role for ArfGAP1 as a restriction factor of host–pathogen interactions. Synopsis Mycobacterial uptake into epithelial cell is dependent on the receptor M3R and requires actin rearrangements regulated by Arf1. This pathway is controlled by ArfGAP1, demonstrating its role in the regulation of host‐pathogen interactions. Colonization by M. tuberculosis depends on the M3 muscarinic receptor (M3R) and the activation of Arf1 and PLD1. M3R‐mediated entry of M. tuberculosis into epithelial cells is restricted by the Arf GTPase‐activating protein ArfGAP1. Mycobacterial entry involves rearrangements of the actin cytoskeleton controlled by ArfGAP1. Graphical Abstract Mycobacterial uptake into epithelial cell is dependent on the receptor M3R and requires actin rearrangements regulated by Arf1. This pathway is controlled by ArfGAP1, demonstrating its role in the regulation of host‐pathogen interactions.