Channel Nuclear Pore Complex subunits are required for transposon silencing in Drosophila
- University of Cambridge, United Kingdom
- University of Birmingham, United Kingdom
Abstract
The Nuclear Pore Complex (NPC) is the principal gateway between nucleus and cytoplasm that enables exchange of macromolecular cargo. Composed of multiple copies of ~30 different nucleoporins (Nups), the NPC acts as a selective portal, interacting with factors which individually license passage of specific cargo classes. Here we show that two Nups of the inner channel, Nup54 and Nup58, are essential for transposon silencing via the PIWI-interacting RNA (piRNA) pathway in the Drosophila ovary. In ovarian follicle cells, loss of Nup54 and Nup58 results in compromised piRNA biogenesis exclusively from the flamenco locus, whereas knockdowns of other NPC subunits have widespread consequences. This provides evidence that some nucleoporins can acquire specialised roles in tissue-specific contexts. Our findings consolidate the idea that the NPC has functions beyond simply constituting a barrier to nuclear/cytoplasmic exchange, as genomic loci subjected to strong selective pressure can exploit NPC subunits to facilitate their expression.
Data availability
Sequencing data have been deposited in GEO under accession number GSE152297. Mass Spectrometry data have been deposited to the PRIDE Archive under accessions PXD019670 and PXD019671. Source data files have been provided for Figure 4.
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Channel Nuclear Pore Complex subunits are required for transposon silencing in DrosophilaNCBI Gene Expression Omnibus, GSE152297.
Article and author information
Author details
Victoria R Lawless
Irmgard U Haussmann
Funding
Cancer Research UK (Core funding (A21143))
- Gregory J Hannon
Wellcome Trust (Investigator award (110161/Z/15/Z))
- Gregory J Hannon
Royal Society (Wolfson Research Professor (RP130039))
- Gregory J Hannon
Boehringer Ingelheim Fonds (PhD fellowship)
- Marzia Munafò
Biotechnology and Biological Sciences Research Council
- Matthias Soller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Munafò et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Channel Nuclear Pore Complex subunits are required for transposon silencing in Drosophila
eLife 10:e66321.
https://doi.org/10.7554/eLife.66321
Further reading
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Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
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