bims-nucpor 2021-08-15 papers

Issue of 2021–08–15
five papers selected by
Sara Mingu, Johannes Gutenberg University

Cancer Discov. 2020 Jan;10(1): OF4

MYC Superenhancer-Nuclear Pore Binding Increases MYC-Transcript Export.

An oncogenic superenhancer recruits active MYC to the nuclear pore in colon-cancer cells.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2019-182

Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2108631118. [Epub ahead of print]118(33):

STING facilitates nuclear import of herpesvirus genome during infection.

Yujin Hong, Heena Jeong, Kiwon Park, Sungwon Lee, Jae Youn Shim, Hyewon Kim, Yang Song, Seowoo Park, Hye Yoon Park, V Narry Kim, Kwangseog Ahn.

Once inside the host cell, DNA viruses must overcome the physical barrier posed by the nuclear envelope to establish a successful infection. The mechanism underlying this process remains unclear. Here, we show that the herpesvirus exploits the immune adaptor stimulator of interferon genes (STING) to facilitate nuclear import of the viral genome. Following the entry of the viral capsid into the cell, STING binds the viral capsid, mediates capsid docking to the nuclear pore complex via physical interaction, and subsequently enables accumulation of the viral genome in the nucleus. Silencing STING in human cytomegalovirus (HCMV)-susceptible cells inhibited nuclear import of the viral genome and reduced the ensuing viral gene expression. Overexpressing STING increased the host cell's susceptibility to HCMV and herpes simplex virus 1 by improving the nuclear delivery of viral DNA at the early stage of infection. These observations suggest that the proviral activity of STING is conserved and exploited by the herpesvirus family. Intriguingly, in monocytes, which act as latent reservoirs of HCMV, STING deficiency negatively regulated the establishment of HCMV latency and reactivation. Our findings identify STING as a proviral host factor regulating latency and reactivation of herpesviruses.

Keywords: HCMV; STING; cell susceptibility; nuclear import

DOI: https://doi.org/10.1073/pnas.2108631118

Nucleic Acids Res. 2021 Aug 09. pii: gkab653. [Epub ahead of print]

Nuclear export of plant pararetrovirus mRNAs involves the TREX complex, two viral proteins and the highly structured 5' leader region.

Julie Kubina, Angèle Geldreich, Jón Pol Gales, Nicolas Baumberger, Clément Bouton, Lyubov A Ryabova, Klaus D Grasser, Mario Keller, Maria Dimitrova.

In eukaryotes, the major nuclear export pathway for mature mRNAs uses the dimeric receptor TAP/p15, which is recruited to mRNAs via the multisubunit TREX complex, comprising the THO core and different export adaptors. Viruses that replicate in the nucleus adopt different strategies to hijack cellular export factors and achieve cytoplasmic translation of their mRNAs. No export receptors are known in plants, but Arabidopsis TREX resembles the mammalian complex, with a conserved hexameric THO core associated with ALY and UIEF proteins, as well as UAP56 and MOS11. The latter protein is an orthologue of mammalian CIP29. The nuclear export mechanism for viral mRNAs has not been described in plants. To understand this process, we investigated the export of mRNAs of the pararetrovirus CaMV in Arabidopsis and demonstrated that it is inhibited in plants deficient in ALY, MOS11 and/or TEX1. Deficiency for these factors renders plants partially resistant to CaMV infection. Two CaMV proteins, the coat protein P4 and reverse transcriptase P5, are important for nuclear export. P4 and P5 interact and co-localise in the nucleus with the cellular export factor MOS11. The highly structured 5' leader region of 35S RNAs was identified as an export enhancing element that interacts with ALY1, ALY3 and MOS11 in vitro.

DOI: https://doi.org/10.1093/nar/gkab653

Nat Commun. 2021 Aug 13. 12(1): 4908

Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD.

Shaopeng Wang, Malgorzata J Latallo, Zhe Zhang, Bo Huang, Dmitriy G Bobrovnikov, Daoyuan Dong, Nathan M Livingston, Wilson Tjoeng, Lindsey R Hayes, Jeffrey D Rothstein, Lyle W Ostrow, Bin Wu, Shuying Sun.

C9ORF72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-containing RNA mediates toxicity through nuclear granules and dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG translation. However, it remains unclear how the intron-localized repeats are exported and translated in the cytoplasm. We use single molecule imaging approach to examine the molecular identity and spatiotemporal dynamics of the repeat RNA. We demonstrate that the spliced intron with G-rich repeats is stabilized in a circular form due to defective lariat debranching. The spliced circular intron, instead of pre-mRNA, serves as the translation template. The NXF1-NXT1 pathway plays an important role in the nuclear export of the circular intron and modulates toxic DPR production. This study reveals an uncharacterized disease-causing RNA species mediated by repeat expansion and demonstrates the importance of RNA spatial localization to understand disease etiology.

DOI: https://doi.org/10.1038/s41467-021-25082-9

Mol Neurobiol. 2021 Aug 14.

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.

AnnaMaria Maraschi, Valentina Gumina, Jessica Dragotto, Claudia Colombrita, Miguel Mompeán, Emanuele Buratti, Vincenzo Silani, Marco Feligioni, Antonia Ratti.

The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

Keywords: Amyotrophic lateral sclerosis; Nucleocytoplasmic transport; SUMOylation; Splicing; TDP-43

DOI: https://doi.org/10.1007/s12035-021-02505-8