Tiny Nanocourier that Delivers Molecular Packages to Cell Surface Unveiled

An international research group led by scientists at Pompeu Fabra University has reported new discoveries that help to better understand the nanomachine that controls a process known as constitutive exocytosis, which is the uninterrupted delivery of spherical molecular packages to and fusion with the cell membrane. This is an essential activity present in virtually all organisms to preserve cell fitness and other vital functions such as communication with the cell’s exterior, cell growth and division.

Studying the yeast Saccharomyces cerevisiae the scientists resolved the dynamic architecture of the tiny machine that delivers essential molecular packages to the cell surface. Discovery of this flexible and transient ‘nanocourier’ required the combined power of multiple microscopes and artificial intelligence, yielding unprecedented information of a key process that occurs billions of times per day in our bodies.

Better understanding of exocytosis may have profound implications for the treatment of some infections and rare diseases. Research lead Oriol Gallego, PhD, leader of the Biophysics in Cell Biology Group at the UPF Department of Medicine and Life Sciences (MELIS), said, “despite being one of the largest nanomachines in the cell, its short lifespan and dynamism made it very challenging to capture.”

Gallego and colleagues reported on their findings in Cell, in a paper titled “Continuum architecture dynamics of vesicle tethering in exocytosis.”

“Constitutive exocytosis (hereafter exocytosis), the uninterrupted transport of secretory vesicles to and subsequent fusion with the plasma membrane (PM), is an essential cellular process for nearly all eukaryotes,” the team wrote. “Exocytosis is critical for the preservation of PM homeostasis, cell growth, and cell division.”

Every day, every cell of our body transports between 10,000–100,000 of these spherical packages to the cell surface to fulfill cellular processes that require the release or display of any molecule on the outside of the cell, such as the secretion of enzymes and hormones, repairing wounds on the cell surface or simply because the cell needs to grow, move or change its shape. Therefore, the delivery of packages to the surface is essential because it is linked to many vital processes that the cell undergoes daily. Central to this intricate process is tethering, which is the finely tuned docking of cargo-loaded vesicles with the plasma membrane, the team further explained.

Despite being vital for the cell, studying exocytosis hasn’t previously been possible in detail. Gallego’s lab, in collaboration with Carlo Manzo, PhD, at the Universitat de Vic, Daniel Castaño, PhD, at the Instituto Biofisika, and Jonas Ries, PhD, at Max Perutz Labs, combined advanced light and electron microscopes with image analysis using artificial intelligence, to resolve the 3D organization of this nanomachine, and filmed how it quickly changes its structure during the delivery of spherical packages. Gallego added, “The function of this nanocourier is so important that it is very rare to find it mutated in patients as its alteration would normally impair the viability of the embryo.”

At the core of this nanomachine, the concerted motion of seven protein assemblies known as exocysts builds a flexible ring that holds the spherical packages in place upon their arrival at their destination: the cell surface. “The exocyst, a conserved heterooctameric protein complex, is the main component of tethering,” the authors noted. “We found that seven exocysts form a flexible ring-shaped ExHOS that tethers vesicles at <45 nm from the PM.”

Co-senior Marta Puig-Tintó, PhD, one of the main authors of the study, further explained, “We have named this nanocourier ExHOS, standing for exocyst higher-order structure. The ExHOS features three checkpoints and a mechanism of disassembly that ensures that the delivery of molecular packages continues at the required speed.”

Co-senior author Sasha Meek, PhD, added, “It is as if every time the cell needs to deliver a heavy package, a team of seven strong couriers work together to do so. Because the package is so heavy, they can’t just drop it all at once and have to lower it in three steps. And when they’re finished, they need confirmation of receipt so that the team of couriers can break up and go on to make other deliveries.”

Increasing what is understood about exocytosis goes far beyond the mere desire to know, and could one day affect many fields of applied science. Plants, for example, need the ExHOS to defend cells against microbial invasion. Hence, many phytopathogens have developed mechanisms to attenuate plant immunity by attacking the ExHOS. A good example is Magnaporthe oryzae, also known as rice blast fungus, which causes the loss of up to a third of the world’s rice production.

In humans, several viruses such as SARS-CoV-2, HIV, or pathogenic bacteria, such as Salmonella, behave similarly and hijack exocytosis during infection. “Beyond its canonical role in exocytosis, the exocyst is involved in the secretion of exosomes and herpesviruses,” the researchers stated. “Not limited to secretory processes, it is a key player in autophagy, host invasion by pathogens (e.g., Salmonella typhimurium), and it is both a pathogen target and an immune receptor in plants. Together, these roles highlight the exocyst’s central importance across diverse biological pathways in both biomedical and agricultural contexts.

Even mild alterations of ExHOS components are linked to human diseases. Though infrequent, mutations in components of the nanocourier cause rare diseases related to neurodevelopmental disorders. In other cases the ExHOS participates in cell invasion in metastatic cancers.

“Despite being small in size, the cell interior is a vast space full of enigmatic nanomachines that have never been observed because of the limitations of current microscopy tools,” Marta Puig-Tintó commented. ”But I think that the future lies in integrating various imaging technologies with the power of new computational tools like AI to “make the invisible visible.”

In their report the authors concluded, “Overall, this study provides quantitative insights into the biophysical principles that drive tethering of secretory vesicles. Given the exocyst’s central role across multiple cellular processes and diseases, these insights could help advance our understanding of the exocyst’s mechanism of action across biology more generally.”

Gallego added, “With these new opportunities, we have unveiled a fundamental and vital cellular process. It’s like explaining how oxygen is exchanged during breathing or how the periodicity of the heartbeat is maintained. It might not have an immediate application, but the discovery of this nanomachine will facilitate future research to find solutions to severe biomedical and biotechnological problems.”

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