Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses

Monwan, Warunthorn; Kawasaki, Takumi; Hasan, Zobaer; Ori, Daisuke; Kawai, Taro

doi:10.1016/j.bbrc.2019.11.035

Cited by 13 publications

(10 citation statements)

References 25 publications

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“…SMAD4 has a critical role in T-cell function and is required in T-cell-mediated autoimmunity and tumour rejection [ 46 ]. NUP93 is also known to regulate antiviral innate immune responses [ 47 ] and is expressed in peripheral blood mononuclear cells as well as in the kidney [ 10 ]. This apparent link between the immune system and other nucleoporins, together with NUP93 expression in mononuclear cells, supports a relationship with immune function as does the detection of anti-NUP210 and -NUP62 antibodies in primary biliary cirrhosis, systemic lupus erythematosus, autoimmune myositis and rheumatic diseases [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model

et al. 2022

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Background Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. Methods Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Results Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. Conclusion We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

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Section: Discussionmentioning

confidence: 99%

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model

et al. 2022

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“…Nup93 is a nucleoporin that mediates mito viral immunity by preventing TBK1 to IRF3 to IFNβ transcription [ 69 ]. Nup93 is a nucleoporin that mediates mitochondrial activated TBK1 import to activate IRF3 and IFNB as part of innate immunity to retroviruses that Nlrx1 blocks [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Stress Decreases Host Viral Resistance and Increases Covid Susceptibility in Embryonic Stem Cells

Abdulhasan

Ruden

Rappolee

et al. 2021

Stem Cell Rev and Rep

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Graphical Abstract Stress-induced changes in viral receptor and susceptibility gene expression were measured in embryonic stem cells (ESC) and differentiated progeny. Rex1 promoter-Red Fluorescence Protein reporter ESC were tested by RNAseq after 72hr exposures to control stress hyperosmotic sorbitol under stemness culture (NS) to quantify stress-forced differentiation (SFD) transcriptomic programs. Control ESC cultured with stemness factor removal produced normal differentiation (ND). Bulk RNAseq transcriptomic analysis showed significant upregulation of two genes involved in Covid-19 cell uptake, Vimentin (VIM) and Transmembrane Serine Protease 2 (TMPRSS2). SFD increased the hepatitis A virus receptor (Havcr1) and the transplacental Herpes simplex 1 (HSV1) virus receptor (Pvrl1) compared with ESC undergoing ND. Several other coronavirus receptors, Glutamyl Aminopeptidase (ENPEP) and Dipeptidyl Peptidase 4 (DPP4) were upregulated significantly in SFD>ND. Although stressed ESC are more susceptible to infection due to increased expression of viral receptors and decreased resistance, the necessary Covid-19 receptor, angiotensin converting enzyme (ACE)2, was not expressed in our experiments. TMPRSS2, ENPEP, and DPP4 mediate Coronavirus uptake, but are also markers of extra-embryonic endoderm (XEN), which arise from ESC undergoing ND or SFD. Mouse and human ESCs differentiated to XEN increase TMPRSS2 and other Covid-19 uptake-mediating gene expression, but only some lines express ACE2. Covid-19 susceptibility appears to be genotype-specific and not ubiquitous. Of the 30 gene ontology (GO) groups for viral susceptibility, 15 underwent significant stress-forced changes. Of these, 4 GO groups mediated negative viral regulation and most genes in these increase in ND and decrease with SFD, thus suggesting that stress increases ESC viral susceptibility. Taken together, the data suggest that a control hyperosmotic stress can increase Covid-19 susceptibility and decrease viral host resistance in mouse ESC. However, this limited pilot study should be followed with studies in human ESC, tests of environmental, hormonal, and pharmaceutical stressors and direct tests for infection of stressed, cultured ESC and embryos by Covid-19. Supplementary Information The online version contains supplementary material available at 10.1007/s12015-021-10188-w.

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“…Nup93 has also been linked to this same pathway. In this case, ablation of Nup93 has been shown to impair the phosphorylation and nuclear translocation of IRF3, and to decrease the production of IFNβ and CXCL10 (Monwan et al, 2020).…”

Section: Box 2 Npcs Aging and Neurodegenerationmentioning

confidence: 97%

“…Interestingly, many of the alterations in T-and B-cell function recover with activation or immunization, suggesting that animals with low levels of Sec13 expression can still generate normal immune responses. Sec13 has also been shown to be involved in the RIG-I-like receptor (RLR)mediated antiviral cellular response (Chen et al, 2018;Monwan et al, 2020). The RLR signaling cascade starts with the recognition and binding of viral RNA by the cytoplasmic RLRs, which activate a downstream signaling cascade leading to the transcription of proinflammatory cytokine genes and type I IFN genes that mediate the antiviral response (Loo and Gale, 2011).…”

Section: Box 2 Npcs Aging and Neurodegenerationmentioning

confidence: 99%

Nuclear pore complexes in development and tissue homeostasis

Guglielmi

Sakuma²,

D’Angelo

2020

Development

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Nuclear pore complexes are multiprotein channels that span the nuclear envelope, which connects the nucleus to the cytoplasm. In addition to their main role in the regulation of nucleocytoplasmic molecule exchange, it has become evident that nuclear pore complexes and their components also have multiple transport-independent functions. In recent years, an increasing number of studies have reported the involvement of nuclear pore complex components in embryogenesis, cell differentiation and tissue-specific processes. Here, we review the findings that highlight the dynamic nature of nuclear pore complexes and their roles in many cell type-specific functions during development and tissue homeostasis.

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Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses

Cited by 13 publications

References 25 publications

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model

Stress Decreases Host Viral Resistance and Increases Covid Susceptibility in Embryonic Stem Cells

Nuclear pore complexes in development and tissue homeostasis

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