Evolutionary robustness of cell polarity during molecular diversification.

Descripción del proyecto

Investigación de la robustez de la polaridad celular durante la evolución

Las células funcionan como intrincadas máquinas, con proteínas que interactúan para realizar tareas esenciales. Sorprendentemente, especies estrechamente emparentadas pueden carecer de proteínas clave y mantener al mismo tiempo funciones celulares básicas. Las investigaciones indican que las levaduras pueden adaptarse a la pérdida de una proteína crucial eliminando otras proteínas, con lo que se restablece la polaridad celular y se influye en múltiples procesos biológicos. El equipo del proyecto PolarRobustness, financiado por el Consejo Europeo de Investigación, estudiará las redes de polaridad evolucionadas en la levadura en ciernes. Examinará cómo la polaridad celular se mantiene robusta a lo largo del tiempo evolutivo analizando los cambios en el número de copias de proteínas, las modificaciones postraduccionales (PTM, por sus siglas en inglés) y la autoorganización. En el proyecto se utilizarán la secuenciación de transposones para el análisis celular, la microscopía de células vivas para evaluar la estabilidad de la polaridad y la espectrometría de masas para estudiar la expresión génica y las interacciones proteínicas.

Objetivo

Cells are often viewed as intricate machines, in which specific proteins work together in a tightly coordinated fashion to give rise to cellular functions. Surprisingly however, some proteins that are essential for core cellular functions in one species are absent in closely related species, while the core function itself is maintained. How this robustness is achieved, while the underlying molecular networks dramatically diversify during evolution is currently not understood. As a post-doc I showed that the polarity network in yeast can evolutionarily adapt to the loss of an important protein by losing three more proteins. My lab showed that these losses repair polarity through a collective adaptive response, affecting many cellular processes rather than only a few proteins. How do intricate cellular networks collectively achieve such evolutionary robustness?

We will address this question with a library of experimentally evolved polarity networks in budding yeast to (1) investigate how general a collective adaptive response is, (2) examine which spatiotemporal aspects of polarity establishment are evolutionary robust, (3) determine how changes in (i) protein copy-numbers, (ii) post-translational modifications (PTMs), and (iii) buffering by self-organization, contribute to evolutionary robustness, and (4) dissect the molecular mechanisms. We will use transposon sequencing to identify the cellular processes involved, live cell microscopy to compare the robustness of various aspects of polarity, and mass spectrometry to compare changes in gene expression, PTMs and interaction partners. We will use multiscale simulations, rooted in statistical physics and constrained by our experimental results, to dissect how molecular changes propagate through the polarity network to achieve evolutionary robustness.

Our approach will go beyond yeast polarity, because it can be applied to any functional protein network to deepen our understanding of how life works and evolves.