bims-nucpor 2022-05-22 papers

Issue of 2022–05–22
five papers selected by
Sara Mingu, Johannes Gutenberg University

Nucleus. 2022 Dec;13(1): 170-193

Spelling out the roles of individual nucleoporins in nuclear export of mRNA.

Mark Tingey, Yichen Li, Wenlan Yu, Albert Young, Weidong Yang.

The Nuclear Pore Complex (NPC) represents a critical passage through the nuclear envelope for nuclear import and export that impacts nearly every cellular process at some level. Recent technological advances in the form of Auxin Inducible Degron (AID) strategies and Single-Point Edge-Excitation sub-Diffraction (SPEED) microscopy have enabled us to provide new insight into the distinct functions and roles of nuclear basket nucleoporins (Nups) upon nuclear docking and export for mRNAs. In this paper, we provide a review of our recent findings as well as an assessment of new techniques, updated models, and future perspectives in the studies of mRNA's nuclear export.

Keywords: Nucleocytoplasmic transport; mRNA biology; super-resolution light microscopy

DOI: https://doi.org/10.1080/19491034.2022.2076965

Mol Genet Genomic Med. 2022 May 15. e1966

Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome.

Erica L Macke, Joel A Morales-Rosado, Sarah K Macklin-Mantia, Christopher T Schmitz, Björn Oskarsson, Eric W Klee, Klaas J Wierenga.

BACKGROUND: Achalasia-addisonianism-alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD-repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction.
METHODS: Whole-exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant.
RESULTS: Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow-up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants.
CONCLUSIONS: Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.

Keywords: achalasia; alacrima; aladin; allgrove; whole-exome sequencing

DOI: https://doi.org/10.1002/mgg3.1966

Mol Hum Reprod. 2022 May 18. pii: gaac017. [Epub ahead of print]

Nucleoporin37 may play a role in early embryo development in human and mice.

Yawen Peng, Jiandong Shen, Yan Gao, Wangjuan Dai, Shuang Liang, Jing Chen, Li Gao, Yuting Lin, Lingbo Cai, Lianju Qin, Yugui Cui, Jiayin Liu, Feiyang Diao.

Maternal-effect genes (MEGs) play an important role in maintaining the survival and development of mammalian embryos at the cleavage stage after fertilization. Despite long-term efforts, the MEGs that regulate preimplantation embryo development remain largely unknown. Here, using Whole-exome sequencing (WES) and homozygosity mapping, we identified a potential candidate gene associated with early embryo development: nucleoporin37 (NUP37), a nucleoporin gene that encodes a member of the nuclear pore complexes (NPCs) and regulates nuclear pore permeability and nucleocytoplasmic transport. Moreover, we determined the temporal and spatial expression patterns of Nup37 in mouse oocytes and early embryos, and explored the role of NUP37 in oocyte maturation and preimplantation embryo development. Immunoprecipitation assays confirmed that YAP1 binds to TEAD4 and NUP37. Furthermore, Nup37 gene knockdown reduced the nuclear import of YAP1 and downregulated the expression of YAP1-TEAD pathway downstream genes Rrm2 and Rpl13 in early embryos. Our study provides evidence that maternal NUP37 contributes to the nuclear import of YAP1 and then activates the YAP1-TEAD pathway, a signaling pathway essential for zygotic genome activation (ZGA). Nup37 may be a key gene involved in preimplantation embryo development in mammals.

Keywords: MEGs; NUP37; YAP1-TEAD pathway; ZGA; early embryo development

DOI: https://doi.org/10.1093/molehr/gaac017

Commun Biol. 2022 May 19. 5(1): 483

SARS-CoV-2 ORF6 disrupts nucleocytoplasmic trafficking to advance viral replication.

Yoichi Miyamoto, Yumi Itoh, Tatsuya Suzuki, Tomohisa Tanaka, Yusuke Sakai, Masaru Koido, Chiaki Hata, Cai-Xia Wang, Mayumi Otani, Kohji Moriishi, Taro Tachibana, Yoichiro Kamatani, Yoshihiro Yoneda, Toru Okamoto, Masahiro Oka.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 is an antagonist of interferon (IFN)-mediated antiviral signaling, achieved through the prevention of STAT1 nuclear localization. However, the exact mechanism through which ORF6 prevents STAT1 nuclear trafficking remains unclear. Herein, we demonstrate that ORF6 directly binds to STAT1 with or without IFN stimulation, resulting in the nuclear exclusion of STAT1. ORF6 also recognizes importin α subtypes with different modes, in particular, high affinity to importin α1 but a low affinity to importin α5. Although ORF6 potentially disrupts the importin α/importin β1-mediated nuclear transport, thereby suppressing the nuclear translocation of the other classical nuclear localization signal-containing cargo proteins, the inhibitory effect of ORF6 is modest when compared with that of STAT1. The results indicate that the drastic nuclear exclusion of STAT1 is attributed to the specific binding with ORF6, which is a distinct strategy for the importin α1-mediated pathway. Combined with the results from a newly-produced replicon system and a hamster model, we conclude that SARS-CoV-2 ORF6 acts as a virulence factor via regulation of nucleocytoplasmic trafficking to accelerate viral replication, resulting in disease progression.

DOI: https://doi.org/10.1038/s42003-022-03427-4

Elife. 2022 May 17. pii: e77646. [Epub ahead of print]11

Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory.

Bethany Sump, Donna G Brickner, Agustina D'Urso, Seo Hyun Kim, Jason H Brickner.

For some inducible genes, the rate and molecular mechanism of transcriptional activation depends on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation and requires both changes in chromatin structure and recruitment of poised RNA Polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.

Keywords: S. cerevisiae; chromosomes; gene expression; genetics; genomics

DOI: https://doi.org/10.7554/eLife.77646