- A study led by Miguel Sánchez-Alvarez from IIBM uncovers a mechanism that allows for the coordination between the endoplasmic reticulum and the cytoskeleton, which is essential for cell differentiation and proper functioning
- The finding, published in Cell Reports, offers a new perspective on the cellular and molecular processes involved in various diseases, including neurodegenerative syndromes, and could contribute to the development of more effective therapeutic strategies
The inside of our cells is organized into different compartments, known as "organelles", each with specific functions. One of these organelles is the endoplasmic reticulum (ER), a complex network of membranes that performs essential tasks, like the formation and maturation of at least 30% of the proteins fabricated by the cell. This includes proteins that are located on the cell's surface, and those that are secreted outside the cell. The architecture of this network (shown in the accompanying image) must adapt to the shape of the cell, which can vary from small spherical lymphocytes to neurons with extensions that can be several centimeters long. Additionally, the ER has to adjust to the changing needs of the cell: when the ER isn’t functioning optimally—a situation known as “ER stress”—cells tend to restructure it and increase its volume.
High-resolution confocal microscopy of the endoplasmic reticulum in a green monkey kidney cell
It has long been known that precise control over the architecture of this membrane network is crucial for the survival and proper functioning of the different cell types in the body. However, how this control is carried out and how it is coordinated with changes in cell shape has largely remained a mystery.
A recent study led by scientist Miguel Sánchez from the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), a mixed center of the Consejo Superior de Investigaciones Científicas (CSIC) and the Universidad Autónoma de Madrid (UAM), and published in Cell Reports, describes a key mechanism for the coordinated control of cell architecture. The researchers used an advanced high-content microscopy methodology, which allows them to capture images of the ER in hundreds of thousands of cells and analyze its structure in an automated way. This makes it possible to perform screenings where the expression of thousands of genes is knocked down to study their impact on cell function in a reasonable amount of time.
The study revealed that the PERK protein plays a broader role than previously thought. Not only does it limit the production of new proteins when activated by ER stress, but it is also essential for the proper accommodation of ER expansion within the cell volume. “One of the first unexpected findings of this study was that when PERK is activated, it not only reduces protein synthesis but also relaxes the anchoring between the ER and the microtubules of the cytoskeleton, allowing the ER to expand and distribute itself properly within the cell,” explains Miguel Sánchez. The microtubules involved in the process of attachment to the ER are the so-called non-centrosomal microtubules, which are related to essential cell functions like orientation and cell polarization.
The researchers wondered whether PERK activation would also influence the stability of the microtubules themselves. “This led to another unexpected finding,” points out the co-leader of the study. “We discovered that the degree of attachment between the ER and the microtubules, which is strongly influenced by PERK activity, also affects the stability of these microtubules.” In cells subjected to ER stress—such as after exposure to tunicamycin, a substance that causes the accumulation of immature proteins in the ER—PERK deactivates the protein synthesis machinery and weakens the attachment between the ER and the microtubules, facilitating its physical expansion. But weakening the ER-microtubule attachment has an additional effect: it decreases the stability of the non-centrosomal microtubules themselves, in a negative feedback process. This confirms that the control of ER architecture and the stability and dynamics of the microtubules are closely coordinated. “And importantly, we can artificially manipulate this system,” concludes Sánchez.
A New Piece in the Puzzle of Multiple Diseases
This dynamic system also explains another remarkable observation from the study. “The morphology and movement behavior of the cell are partly conditioned by the functional state of the ER and the control of protein synthesis through PERK,” explains Miguel Sánchez. “When cells experience high ER stress and activate PERK, they reduce the attachment between the ER and the non-centrosomal microtubules to allow for expansion. However, this also reduces the stability and abundance of these microtubules, making the cells adopt a more static state, with less polarized organization and decreased migration ability,” he adds. “In contrast, cells with reduced PERK activity maintain a high degree of attachment between the ER and the microtubules. This may make it harder for the ER to reorganize, but it also stabilizes the non-centrosomal microtubules, promoting a morphology with larger and more stable protrusions.”
These findings are highly relevant given the importance of these mechanisms in cell physiology, and have important implications for neurological diseases like spastic paraparesis or certain forms of dementia. Additionally, the authors observed that reducing PERK activity stabilizes axon formation during neuronal differentiation, which could influence processes like memory and learning. It could also help better understand the role of ER stress in cancer. “The ability of cancer cells to adapt to this imbalance not only influences their survival but can also modify their migratory behavior, a key factor in metastasis,” explains Chris Bakal, co-director of this research. “The level of detail we’re reaching in understanding these processes—and, most importantly, how they are interrelated—could pave the way for new therapeutic strategies across various diseases,” concludes Miguel Sánchez.
This research involved collaboration with the laboratories of Chris Bakal at the Institute of Cancer Research (ICR) in London, and Miguel Ángel del Pozo and Jesús Vázquez at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, and was funded by: The Wellcome Trust, Cancer Research UK, the Asociación Española Contra el Cáncer, the Ministry of Science, Innovation, and Universities, and the Fundación La Caixa.
Given the significance of this work, the CSIC Communications Department has published this press release on its Actualidad page.
Cover Image: Superresolution micrographs of a human breast epithelial cell, showing the interrelated architecture of the endoplasmic reticulum (ER; green hue) and the microtubule cytoskeleton (MTs; magenta hue).
Miguel Sánchez-Alvarez, Chris Bakal, et al,. PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape. Cell Reports, 2025. https:// doi.org/10.1016/j.celrep.2025.115590