Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations

Abstract

The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.

Depletion of nuclear pore protein NUP210 suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response

“…In response to a foreign ECM environment, metastatic cells may exploit this mechanism through repositioning TADs to the nuclear pore for robust transcription of mechanosensitive genes, which then promote their migration into distant organs in an autocrine fashion. In fact, two recent studies have suggested that Nup210-deficient mice possesses defective T-cell receptor signaling 64,75 . It is highly likely that NUP210 might promote metastasis through rapid transcriptional activation of mechanosensitive, immune component genes.…”

“…Apart from providing structural support and nucleocytoplasmic transport 57 , the role of the nuclear pore complex in developmental gene regulation has drawn much attention recently [58][59][60][61] . Although NUP210 has been implicated in muscle differentiation 28,62 , cellular reprogramming 63 , and T cell signaling 64,65 , its function in human cancer was unknwon. Here, we have identified Nup210 as a potential metastasis susceptibility gene for human ER+ breast cancer patients and demonstrated a previously unrecognized role of nuclear pore proteins in sensing the mechanical stress of the extracellular matrix.…”

“…Heterochromatic foci were segmented using DAPI staining and used to create a distance map. DNA FISH spots were segmented and the distance to the nearest heterochromatic foci was calculated and plotted as box 75 plots (bottom and top of the box denote first and third quartile respectively, whiskers denote -/+ 1.5 interquartile range (IQR), horizontal lines denote median values). p-values were calculated using a two-tailed Mann-Whitney U-test.…”

Nuclear pore complexes in development and tissue homeostasis

“…Recently, two independent studies have revealed a role for the transmembrane Nup Nup210 in T-cell homeostasis (Borlido et al, 2018;van Nieuwenhuijze et al, 2018). Loss of Nup210 has been found to cause a severe decrease in the naïve CD4 + T-cell population.…”

“…In Drosophila, another cytoplasmic filament protein Mbo (the homolog of human Nup88) is required for the immune response against bacterial infection. Besides leading to alterations in the CNS, oogenesis and tracheal development, ablation of mbo results in a severe immune deficiency, owing to alterations in the nuclear import of factors key for the activation of the immune response (Uv et al, 2000).…”