The cell is the basic unit of life and, at the same time, an extremely complex and sophisticated machine in which thousands of proteins, among other components, are strategically located in different compartments where they carry out cellular functions. The cell must ensure that its proteins are properly distributed to their place of function, because if this fails and they do not reach their destination, the proteins either stop working or get out of control, causing diseases ranging from genetic syndromes to cancer or neurological diseases. Therefore, it is important to investigate how proteins are distributed towards their functional destination.
It was previously suggested that, the lipids that make up the cell membranes may also play an additional role in the distribution of proteins within cells. This work by the Seville researchers solves this enigma of basic biology, demonstrating for the first time how lipids can distribute proteins at the cellular level.
An international team of scientists, coordinated by the Seville Institute of Biomedicine (IBiS) and the University of Seville has solved one of the hitherto unresolved enigmas of basic biology: how exactly do lipids distribute proteins within a cell? To do this, they used a new, completely innovative microscopy technology, which they applied to “mutant” cells they designed in their laboratory. Researchers have observed how lipids distribute proteins within cells, a discovery that could open the door to understanding the causes of protein transport related diseases, such as cancer or neurodegenerative diseases. lipid-based protein cargo sorting into selective export sites in the secretory pathway and reveals the critical importance of the acyl chain length for sorting selectivity. We took advantage of a powerful and cutting-edge microscopy technology called SCLIM to demonstrate in yeast that newly synthesized Gas1-GFP, a major plasma membrane GPI-AP having a very long acyl chain (C26) ceramide lipid moiety, is clustered into discrete ER zones associated with specific ERES, whereas transmembrane secretory proteins distribute throughout the ER membrane.
This discovery represents a major advance in understanding how proteins are distributed in cells to perform their vital functions, and could open the door to understanding the causes of diseases associated with failures in protein distribution at the cellular level: from cancer to neurodegenerative diseases, such as Alzheimer’s.
The study was carried out by the Department of Cell Biology’s Membrane Trafficking research group, part of the Faculty of Biology of the University of Seville and the IBiS, led by Professor Manuel Muñiz Guinea, in collaboration with the universities of Hiroshima (Japan), Geneva and Fribourg (Switzerland). The RIKEN Institute in Japan, where the “Super-resolution Living Cell Microscopy” Laboratory is located, also participated in this project. This is a unique facility in the world which conducted analyses using a high resolution fluorescence microscope that allows the study of very fast and dynamic processes in living cells on an incredibly small scale.
The proteins are manufactured in a compartment of the cell and then have to be distributed correctly by exiting through specific “doors.” In this study, scientists from Seville discovered that membrane lipids are responsible for selecting and directing certain proteins to the correct exit doors.
To make this discovery, they designed a “mutant cell” that was programmed to manufacture a shortened version of cellular lipids called ceramides. The researchers suspected that the length of these lipids could be a determining factor in choosing the appropriate exit door.
And that’s exactly what we found. Thanks to the short ceramides we generated, we were able to demonstrate for the first time that lipids are only able to guide proteins during transport if they are the right length. Moreover, by using such a powerful ‘super microscope’ we were able to capture for the first time on an ultra small scale andin vivohow proteins exit through these molecular doors.
As a curiosity, this study was carried out using yeast cells (the same unicellular fungus used to make bread, beer and wine) as a model organism, because, being eukaryotic cells just like ours, they perform the same basic cellular processes in a very similar way, so the observations can be extrapolated to human cells.
In conclusion,the article published in Science Advances has also served to demonstrate that lipids and proteins influence each other to self-organize together within the cell, and points out that the mechanism they have discovered and used for this could be used in other processes, such as the entry and exit of certain viruses from the cell, as well as in the formation of exosomes (extra-cellular lipid vesicles involved in communication between cells, particularly in cancer).
Sofia Rodriguez-Gallardo, Kazuo Kurokawa, Susana Sabido-Bozo, Alejandro Cortes-Gomez, Atsuko Ikeda, Valeria Zoni, Auxiliadora Aguilera-Romero, Ana Maria Perez-Linero, Sergio Lopez, Miho Waga, Misako Araki, Miyako Nakano, Howard Riezman, Kouichi Funato, Stefano Vanni, Akihiko Nakano, Manuel Muñiz. Ceramide chain length-dependent protein sorting into selective endoplasmic reticulum exit sites. Science Advances 11 Dec 2020: Vol. 6, no. 50, eaba8237, DOI: 10.1126/sciadv.aba8237Go To Science Advances