Bacterial intracellularly active toxins: Membrane localisation of the active domain

Abstract

Numerous bacterial toxins exert their activity by inactivating or modulating a specific intracellular host target. For this purpose, these toxins have developed efficient strategies to overcome the different host cell defences including specific binding to cell surface, internalisation, passage through the endosome or plasma membrane, exploiting intracellular trafficking and addressing to intracellular targets. Several intracellularly active toxins deliver an active domain into the cytosol that interacts with a target localised to the inner face of the plasma membrane. Thus, the large clostridial glucosylating toxins (LCGTs) target Rho/Ras-GTPases, certain virulence factors of Gram negative bacteria, Rho-GTPases, while Pasteurella multocida toxin (PMT) targets trimeric G-proteins. Others such as botulinum neurotoxins and tetanus neurotoxin have their substrate on synaptic vesicle membrane. LCGTs, PMT, and certain virulence factors from Vibrio sp. show a particular structure constituted of a four-helix bundle membrane (4HBM) protruding from the catalytic site that specifically binds to the membrane phospholipids and then trap the catalytic domain at the proximity of the membrane anchored substrate. Structural and functional analysis indicate that the 4HBM tip of the Clostridium sordellii lethal toxin (TcsL) from the LCGT family contain two loops forming a cavity that mediates the binding to phospholipids and more specifically to phosphatidylserine. K E Y W O R D S Bacterial virulence factors, cell membrane, large clostridial glucosylating toxins, MARTX toxins, Pasteurella multocida toxin, phospholipids, Rho/Ras-GTPases

Megaviruses contain various genes encoding for eukaryotic vesicle trafficking factors

“…This is in stark contrast to most known viruses, which are much smaller and have more streamlined genomes [13]This, which had virus with unprecedented genetic complexity, was named Acanthamoeba polyphaga mimivirus , for microbe-mimicking virus, as it enters the host cell like a bacterium via phagocytosis because of its sheer size [14–17]. Note that many smaller, classical enveloped viruses such as influenza virus or SARS-CoV-2 [18] and bacterial toxins such as clostridial neurotoxins [19] enter eukaryotic cells by endocytosis. These viruses and toxins have dedicated docking proteins that bind specifically to cellular surface receptors.…”

Lipid binding by N-terminal motif mediates plasma membrane localization ofBordetellaeffector protein BteA

“…This domain is characterized by a deep electropositive binding pocket and surrounding membrane-penetrating leucine residues [4,5]. Another domain termed 4HBM for four-helix bundle membrane localization domain is shared by multiple bacterial toxins, including Pasteurella multocida mitogenic toxin (PMT), multifunctional-autoprocessing RTX toxins (MARTX), and large clostridial glucosyltransferase toxins exemplified by Clostridium difficile toxin A (TcdA) and toxin B (TcdB), and C. sordellii lethal toxin (TcsL) [1,[6][7][8]. The phospholipid-binding site of 4HBM 90 is located at the apex of the structure, the so-called bundle tip, which is formed by two protruding loops, loop (L1) connecting helices 1 and 2, and loop 3 (L3) in between helices and 4.…”

Megaviruses contain various genes encoding for eukaryotic vesicle trafficking factors

“…13 This, which had virus with unprecedented genetic complexity, was named Acanthamoeba polyphaga mimivirus, for microbemimicking virus, as it enters the host cell like a bacterium via phagocytosis because of its sheer size. [14][15][16][17] Note that many smaller, classical enveloped viruses such as influenza virus or SARS-CoV-2 18 and bacterial toxins such as clostridial neurotoxins 19 enter eukaryotic cells by endocytosis. These viruses and toxins have dedicated docking proteins that bind specifically to cellular surface receptors.…”