ReviewCellular mechanosensing: Getting to the nucleus of it all
Introduction
Mechanotransduction describes the cellular and molecular processes of converting mechanical stimuli into biochemical signals. Since the discovery of stretch sensitive ion channels, the field has rapidly expanded, leading to the discovery of various force sensitive proteins within the cytoplasm and plasma membrane, such as titin, talin, vinculin, and p130Cas (Seifert and Grater, 2013). Disturbed cellular mechanotransduction causes numerous defects on the cell, tissue, and organ level (Jaalouk and Lammerding, 2009); thus, it only seems logical that the human heart, which beats on average 2.5 billion times over the course of a lifetime, requires tightly regulated and robust mechanoregulation. Beyond this, the importance of mechanoelectric feedback adds another layer of complexity to cardiac mechanotransduction. For instance, ion channels such as Cav1.2 and the TRP family of ion channels have specific locations in the heart and enable organ level responses to pressure and volume fluctuations by helping regulate action potentials (Takahashi et al., 2013). Connexins, transmembrane proteins important for gap junction formation, may act as effectors to coordinate excitation-contraction coupling (Meens et al., 2013). Beyond this, connexin-43 is upregulated in response to mechanical stimulation and precedes other cell–cell junction formations. While mechanosensing at the plasma membrane and the cytoskeleton has been well studied, our knowledge quickly diminishes as we probe deeper into (cardiac) cells. It is clear that cardiac myocyte nuclei undergo substantial deformations during contraction (Fig. 1); however, one remaining central question in cardiac mechanobiology and mechanobiology in general, revolves around the extent to which the nucleus itself can act as a mechanosensor.
A mechanosensor, as we will define it, is a protein (or, more generally, a cellular structure) that translates a mechanical input into a biochemical output, thereby initiating mechanoresponsive signaling pathways. Typically, molecular mechanosensing involves force induced conformational changes, resulting in altered interaction with binding partners or modulation of (protein) activity. It is well established that the nucleus plays an important role in mechanotransduction signaling, i.e., the process of biochemical signal propagation and processing, as most signaling pathways eventually culminate with nuclear proteins binding to specific genomic elements to modulate transcription. It is also known that the nucleus is mechanically connected to the rest of the cell via LINC (Linker of Nucleoskeleton and Cytoskeleton) complex structures in the nuclear envelope. These complexes are akin to focal adhesions at the plasma membrane, allowing for cytoskeletal and external forces to result in nuclear deformations (Lombardi and Lammerding, 2011). But, the question remains: can mechanically induced nuclear deformations directly control gene expression in a predictable, biologically-meaningful way? If so, what are the molecular mechanisms that enable the nucleus to sense and respond in this way? What are the implications for cardiac function in health and disease? Are there cardiac specific mechanisms for nuclear mechanotransduction?
The emergence of new technologies–ranging from advanced imaging and bioengineering approaches for cell-based assays, to molecular probes that can detect nanoscale forces and deformations–has enabled the scientific community to finally start addressing this important question. In the following sections, we will briefly outline current models of nuclear mechanotransduction before discussing how recent findings, ranging from cellular and subcellular studies to human diseases, and corresponding disease models are beginning to shape a clearer portrait of the nucleus as both a mechanosensor and a central processing hub for mechanoresponsive signaling pathways. Lastly, we will highlight how recent and ongoing advances in technology development will help to further elucidate the fascinating biology of nuclear mechanotransduction and its role in human health and disease.
Section snippets
The nucleus at the center of the cell
A basic overview of the mechanical connectivity linking the nucleus to the rest of the cell and its ECM surroundings (Fig. 2) provides a helpful roadmap for understanding how the nucleus may carry out mechanotransduction processes. The nucleus is encapsulated by a double lipid membrane system, composed of the inner and outer nuclear membrane (INM, ONM), that is studded with nuclear pores. Driven by recent advances in protein isolation, mass spectroscopy, and super-resolution imaging, it is now
The theory – potential mechanisms of nuclear mechanosensing
As we gain a better understanding of the structure and function of the nuclear envelope and interior, we move ever closer to comprehending how the nucleus perceives and responds to force. Based on our current knowledge, a number of (non-mutually exclusive) molecular mechanisms have been proposed that could directly modulate nuclear structure and transcriptional regulation, thereby enabling the nucleus to transduce mechanical forces into biochemical signals (Fig. 3).
The case for nuclear mechanotransduction – getting to the nucleus of it
Cells subjected to mechanical stimuli respond with rapid (<30 min) activation of characteristic ‘mechanosensitive’ genes such as Egr-1, Iex-1, or Pai-1 that often represent immediate early transcription factors that turn on additional genes. Many of these responses appear quite ubiquitous and can be observed in a number of different cell lines, including fibroblasts, myotubes, and neonatal cardiac myocytes (Banerjee et al., 2014, Ho et al., 2013b, Lammerding et al., 2004). Intriguingly, cells
Mutations in nuclear envelope proteins cause dilated cardiomyopathy
Achieving an understanding of the mechanisms underlying human disease is one of the major drivers in biomedical sciences. A powerful illustration of the importance of mechanotransduction comes from the large number of human diseases linked to defects in cellular structure and mechanosensing, including cardiomyopathies, vascular disease, muscular dystrophy, cancer, reversal of the inner organs, and hearing defects (Jaalouk and Lammerding, 2009). Muscle diseases, such as cardiomyopathies and
The road ahead – technology leading the way
The ability to identify specific changes to gene location, chromatin structure, chromatin organization, and transcriptional activity in response to mechanical force would bring much clarity to the specific nuclear mechanotransduction mechanisms at work. Emerging methods and technologies that can relate intranuclear forces with biochemical events such as conformational changes and transcriptional processes, particularly on the single cell level, have the potential to transform the way we study
Outlook & conclusions
We can confidently proclaim that the nucleus plays an important role in cellular mechanotransduction and function, as the many diseases resulting from mutations in nuclear envelope proteins attest. Increasing evidence suggests that the nucleus itself can respond to mechanical forces and deformations, resulting in altered transcriptional regulation and cellular function. However, many of the mechanisms remain unclear and underexplored, including the precise role of nuclear envelope proteins such
Editors’ note
Please see also related communications in this issue by Vostarek et al. (2014) and Dhein et al. (2014).
Acknowledgments
The authors apologize to all authors whose work could not be cited due to space constraints. This work was supported by National Institutes of Health awards [R01 HL082792 and R01 NS59348]; a Department of Defense Breast Cancer Idea Award [BC102152]; a National Science Foundation CAREER award to Lammerding J [CBET-1254846]; and a Pilot Project Award by the Cornell Center on the Microenvironment & Metastasis through Award Number U54CA143876 from the National Cancer Institute, as well as NSF
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