“What our work shows is how a complex at the center of the cell, the ER-Golgi interaction region, controls plasma membrane cholesterol, which is essential for many cellular functions, even essential for life. multicellular,” explains Professor Gisou van der Goot. at the EPFL School of Life Sciences. His group, in collaboration with Giovanni D’Angelo’s group at EPFL, published a study revealing how pathogens exploit a key cellular process to poison cells.
Since pathogens have evolved to hijack many cellular processes from their hosts, studying host-pathogen interactions helps us better understand fundamental biological processes. Here, scientists discovered that the interaction between two key organelles in the cell, the endoplasmic reticulum and the Golgi apparatus, is essential in controlling which lipids are found at the cell membrane. Both organelles play an essential role in the synthesis of new proteins and their transport into the cell.
Researchers set out to determine which proteins are important for the anthrax bacteria’s toxin Bacillus anthracis enter the cell. To do this, they screened a bank of 1,500 genes normally involved in the organization of the cell’s organelles as well as its membrane.
Anthrax infection and ER-Golgi contact sites
Anthrax toxin is composed of three subunits, a protective antigen which allows it to bind to receptors on the target cell, and two enzyme subunits, lethal factor and edema factor, which cause actually damage the cell.
When secreted, the protective antigen binds to two receptors on the cell membrane. It is then cut by furin, an enzyme, and finally associates with other protective antigens to form a pore. This pore allows lethal and edematous factors to enter the cell, where they wreak havoc. Although this process is fairly well mapped, it is unclear which molecules within the cell facilitate all of its steps.
From anthrax to biological discovery
The data from the genes screened landed on two genes and their proteins, called TMED2 and TMED10, both located at the ER-Golgi contact sites, a highly unexpected location when studying a toxin from outside of the cell.
When scientists down-regulated the genes for TMED2 and TMED10, the anthrax toxin lost its ability to form pores. Furthermore, extensive analysis revealed something new in terms of basic cell biology: that both proteins organize large protein supercomplexes at ER-Golgi membrane contact sites, which are responsible for the transfer of cholesterol between the two organelles. If this transfer does not occur, the cholesterol never reaches the cell membrane and is instead stored in fat droplets.
“Overall, this study of anthrax intoxication led to the discovery that remodeling of lipid composition at ER-Golgi interfaces fully controls the formation of functional membrane nanodomains at the cell surface,” conclude the authors. study authors.