Abstract
Cell fate is correlated to mechanotransduction, in which forces transmitted by the cytoskeleton filaments alter the nuclear shape, affecting transcription factor import/export, cells transcription activity and chromatin distribution. There is in fact evidence that stem cells cultured in 3D environments mimicking the native niche are able to maintain their stemness or modulate their cellular function. However, the molecular and biophysical mechanisms underlying cellular mechanosensing are still largely unclear. The propagation of mechanical stimuli via a direct pathway from cell membrane integrins to SUN proteins residing in the nuclear envelop has been demonstrated, but we suggest that the cells’ fate is mainly affected by the force distribution at the nuclear envelope level, where the SUN protein transmits the stimuli via its mechanical connection to several cell structures such as chromatin, lamina and the nuclear pore complex (NPC). In this review, we analyze the NPC structure and organization, which have not as yet been fully investigated, and its plausible involvement in cell fate. NPC is a multiprotein complex that spans the nuclear envelope, and is involved in several key cellular processes such as bidirectional nucleocytoplasmic exchange, cell cycle regulation, kinetochore organization, and regulation of gene expression. As several connections between the NPC and the nuclear envelope, chromatin and other transmembrane proteins have been identified, it is reasonable to suppose that nuclear deformations can alter the NPC structure. We provide evidence that the transmission of mechanical forces may significantly affects the basket conformation via the Nup153-SUN1 connection, both altering the passage of molecules through it and influencing the state of chromatin packing. Finally, we review the known correlations between a pathological NPC structure and diseases such as cancer, autoimmune disease, aging and laminopathies.
Highlights
Cells respond to extracellular environment changes via their mechanosensitive elements, from the adhesion complexes to the nucleus itself (Ribbeck and Görlich, 2002; Wang et al, 2009; Kirby and Lammerding, 2018)
The authors suggested that changes in the nuclear pore complex permeability could be due to nuclear basket rearrangement (García-González et al, 2018). Based on these evidences and due to the interaction of SUN1 with Nup153 (Li and Noegel, 2015), we developed a new model based on the mechanoactivation of NPC, where the nuclear basket portion can act as a stretch-gated structure
Several studies investigated nuclear involvement in the cell mechanotransduction and cell fate but only in recent years the research has been trying to correlate this mechanism with the architecture and function of the NPCs
Summary
Cells respond to extracellular environment changes via their mechanosensitive elements, from the adhesion complexes to the nucleus itself (Ribbeck and Görlich, 2002; Wang et al, 2009; Kirby and Lammerding, 2018). Another constituent of the NPC’s nuclear basket is Nup153 (1475 amino acids) composed of three main domains: (i) the N-terminal domain spanning about 600 amino acids (Duheron et al, 2014), which consists of a nuclear localization signal, a nuclear envelope targeting cassette, an NPC association region and a RNA binding domain (Ball and Ullman, 2005; Al-Haboubi et al, 2011; Duheron and Fahrenkrog, 2015); (ii) a central domain spanning about 250 amino acids consisting of four or five zinc fingers, which tie Nup153 to the distal ring (Duheron et al, 2014); (iii) a C-terminal domain consisting of around 600 amino acids containing ∼30 FxFG-repeats (Walther et al, 2001).
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