Dodgem car like bumping helps vesicular transport system deliver on time

Dr Senthil Arumugam
Dr Senthil Arumugam

Cells are master logisticians when it comes to transporting cargo around their interiors. But just how do cargoes get delivered with a high degree of precision, when the interior of the cell is noisy at microscopic level?

Published recently in Nature Communications, a team of researchers from Monash and Purdue Universities have revealed a novel mechanism by which cells control orderly and timed delivery of molecular cargo to the correct destinations within the cell. Internal cell traffic might look like dodgem cars but the study shows that the rate of bumping precisely determines the maturation rates of the cargo.

The cells in our bodies contain little bubble-like compartments, called endosomes, that transport cargoes such as receptors, nutrients etc. from the cell membrane to various destinations inside. Beyond the fundamental appeal of this complex system, understanding this system is extremely important for human health. For example, many pathogens – bacteria, viruses  – have evolved to ‘hijack’ the cellular transport system to infect; receptors are mis-trafficked in many cancers; and mutations in trafficking machinery proteins result in developmental defects and many genetic disorders.

A movie showing APPL1 endosomes (green) frequently colliding with EEA1 (Magenta) before turning into EEA1 themselves - highlighted by square brackets. This movie was acquired in the Lattice Light-Sheet Microscopy.

One of the organisational orders in the endosomal system is that endosomes ‘mature’ from one ‘flavour’ to another. They do so by biochemical conversions – a process in which a set of molecules on their surfaces are replaced by another. This process is an important step for the endosomes to reach a biochemical state from where cargoes can be routed to their right destinations.

Co-led by Monash Biomedicine Discovery Institute’s Dr Senthil Arumugam and Purdue University’s Professor Srividya Iyer-Biswas, the study reveals that collisions between immature and mature endosomes help trigger the maturation process.

The team used advanced microscopy techniques including Lattice Light-Sheet Microscopy, to watch endosomes bumping into each other inside living cells, combined with theoretical modelling to support a model where, when an immature endosome collides with a mature one, key proteins get transferred over. This “seeds” the immature endosome to start maturing. Blocking this transfer prevents the maturation process, suggesting maturation relies on these collision-induced triggers.

This sophisticated mechanism updates a previously assumed, simple, single endosomal centric model of maturation that could not explain population level dynamics.

The researchers propose this mechanism allows cells to tightly control when endosomes mature. This ensures orderly and timed delivery of molecular cargo to the correct destinations within the cell. These findings provide a new model for how ‘random’ collisions between cellular compartments can regulate an orderly maturation process crucial for cargo transport and delivery in cells. The research reveals that seemingly chaotic movements and collisions can actually kickstart biochemical reactions resulting in precise timing mechanisms.

By uncovering this “trigger and convert” process, the study significantly advances our understanding of the complex logistics that cells use to accurately distribute molecules where they need to go. The study highlights ‘emergent phenomena’ where very predictable outcomes at the scale of the cell emerge out of chaotic processes at the molecular level.

This research exemplifies how newer microscopy techniques can reveal fast events leading to discovery of novel mechanisms. The workflows and analysis tools developed as part of this work will pave way for a variety of cellular transport problems – how do viruses and toxins get transported? How do therapeutic nanoparticles such as mRNA vaccine deliver cargo? What goes wrong with receptor trafficking in cancer and many more. The team have also made all their analysis codes freely available to the scientific community.

Read the paper, published in Nature Communications, titled Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism.

DOI: 10.1038/s41467-023-40428-1

About the Monash Biomedicine Discovery Institute

Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.