Resultados

Although the pathways that regulate how mechanical cues are sensed and transmitted are beginning to be dissected, it remains unknown how these pathways function in concert, particularly within the complexity of a single cell. Current efforts in mechanobiology continue to focus on identifying proteins with mechanosensitive properties. To date, these efforts have revealed several players that function in complex systems encompassing cell adhesions, the cytoskeleton, and the nucleus. Most of what we know about mechanotransduction stems from work on integrin-mediated mechanotransduction, where several core regulators of adhesions have been shown to be force-sensitive (Sun et al., 2016). Similar to adhesions, we are now beginning to see that the nucleus is highly mechanosensitive (Guilluy et al., 2014b; Enyedi et al., 2016) and is home to several force-sensitive proteins including lamin A/C (Swift et al., 2013), emerin (Lammerding et al., 2005), and nuclear pores (Elosegui-Artola et al., 2017). Perhaps most striking about mechanobiology is how seemingly distal regions of the cell are not isolated from mechanical inputs, despite compartmentalization as is seen in organelles. For example, stresses applied through integrins have now been shown to propagate beyond the nuclear lamina, resulting in deformation of chromatin along with concomitant changes in transcriptional activity (Tajik et al., 2016). As the field continues to characterize the individual force-sensitive proteins and systems of the cell, it will be important to remember that the cell is comprised of

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structurally integrated networks of elements that together sense, transmit, and respond to force. In this vein, disruption to obligate proteins of one structure of the cell can indeed affect other separate structures. Thus, studying system-wide cell behavior responses, in addition to molecular signaling events, will be important for evaluating and in understanding these structural networks that signal force.

Lastly, characterizing pathogenic mutations that are associated with laminopathies should be useful toward understanding how nuclear-associated proteins influence cell tension in disease states. This may provide a mechanistic explanation for why somatic mutations within these nuclear-associated genes manifest as disease states in some cells of the body but not all. The diverse pathologies associated with mutations in the LMNA gene alone demonstrate a spectrum of pleiotropic effects caused by this one gene. Similarly diverse pathologies have been associated with mutations in EMD (emerin), SYNE1 and SYNE2 (nesprins 1 and 2), and SUN1 (Janin et al., 2017). Taken together, this supports our need to fully characterize the altered functions caused by mutations within nuclear-associated proteins and understand if changing the stiffness of cell microenvironments can elicit certain phenotypes.

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