Mammalian membrane trafficking as seen through the lens of bacterial toxins

Abstract

A fundamental question of eukaryotic cell biology is how membrane organelles are organised and interact with each other. Cell biologists address these questions by characterising the structural features of membrane compartments and the mechanisms that coordinate their exchange. To do so, they must rely on variety of cargo molecules and treatments that enable targeted perturbation, localisation, and labelling of specific compartments. In this context, bacterial toxins emerged in cell biology as paradigm shifting molecules that enabled scientists to not only study them from the side of bacterial infection but also from the side of the mammalian host. Their selectivity, potency, and versatility made them exquisite tools for uncovering much of our current understanding of membrane trafficking mechanisms. Here, we will follow the steps that lead toxins until their intracellular targets, highlighting how specific events helped us comprehend membrane trafficking and establish the fundamentals of various cellular organelles and processes. Bacterial toxins will continue to guide us in answering crucial questions in cellular biology while also acting as probes for new technologies and applications.

Botulinum toxin intoxication requires retrograde transport and membrane translocation at the ER

“…Our study contradicts the long-established model of BoNT intoxication, which is described in several reviews specifically dedicated to the subject (Dong et al, 2019;Pirazzini et al, 2017Pirazzini et al, , 2016Rossetto et al, 2021). In short, these reviews support the notion that BoNT are molecular machines able to mediate their own translocation across membranes; this notion has also convinced cell biologists interested in toxins and retrograde traffic, who describe BoNT mode of internalisation in their reviews (Mesquita et al, 2020;Williams and Tsai, 2016).…”

“…In short, these reviews support the notion that BoNT are molecular machines able to mediate their own translocation across membranes. This notion has convinced some cell biologists interested in toxins and retrograde membrane traffic, who follows this model of BoNT mode of translocation in their reviews (Mesquita et al, 2020;Williams and Tsai, 2016).…”

Anthrax intoxication reveals that ER-Golgi membrane contact sites control the formation of plasma membrane lipid nanodomains

“…Pathogens have evolved to co-opt existing cellular processes of their hosts. Consequently, studies of host-pathogen interactions are continuously deepening our understanding of fundamental biological processes and have helped uncover ones such as the fusion of synaptic vesicles, dynamics of the actin cytoskeleton, or retrograde transport from the Golgi to the ER (Mañes et al, 2003; Mesquita et al, 2020; Schiavo & van der Goot, 2001). Here, we searched for genes enabling anthrax intoxication, which uncovered proteins involved in compartmentalisation of the plasma membrane.…”

Toxin secretion and trafficking by Mycobacterium tuberculosis

“…Toxin export and/or secretion is often mediated by specialized secretion systems. These molecular machines recognize and transport toxins across bacterial and, sometimes, host cell membranes [2][3][4] . Toxin secretion mechanisms have been described in almost all major bacterial pathogens with the notable exception of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis.…”