bims-nucpor 2023-02-26 papers

Issue of 2023–02–26
four papers selected by
Sara Mingu, Johannes Gutenberg University

Nucleus. 2023 Dec;14(1): 2178184

Nuclear envelope budding and its cellular functions.

Katharina S Keuenhof, Verena Kohler, Filomena Broeskamp, Dimitra Panagaki, Sean D Speese, Sabrina Büttner, Johanna L Höög.

The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.

Keywords: Nuclear import; nuclear envelope budding; nuclear export

DOI: https://doi.org/10.1080/19491034.2023.2178184

Cell Rep. 2023 Feb 22. pii: S2211-1247(23)00145-6. [Epub ahead of print]42(3): 112134

Loss of C9orf72 perturbs the Ran-GTPase gradient and nucleocytoplasmic transport, generating compositionally diverse Importin β-1 granules.

Philip McGoldrick, Agnes Lau, Zhipeng You, Thomas M Durcan, Janice Robertson.

A hexanucleotide (GGGGCC)n repeat expansion in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins, and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 disrupts the Ran-GTPase gradient and NCT in vitro and in vivo. NCT disruption in vivo is enhanced by the presence of compositionally different types of cytoplasmic Importin β-1 granule that exhibit neuronal subtype-specific properties. We show that the abundance of Importin β-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to associate with the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.

Keywords: ALS; C9orf72; CP: Neuroscience; FG-Nups; FTD; G3BP1; Importin; Ran-GTPase; RanGAP; nucleocytoplasmic transport; ubiquitin

DOI: https://doi.org/10.1016/j.celrep.2023.112134

Nat Struct Mol Biol. 2023 Feb 20.

Modeling HIV-1 nuclear entry with nucleoporin-gated DNA-origami channels.

Qi Shen, Qingzhou Feng, Chunxiang Wu, Qiancheng Xiong, Taoran Tian, Shuai Yuan, Jiong Shi, Gregory J Bedwell, Ran Yang, Christopher Aiken, Alan N Engelman, C Patrick Lusk, Chenxiang Lin, Yong Xiong.

Delivering the virus genome into the host nucleus through the nuclear pore complex (NPC) is pivotal in human immunodeficiency virus 1 (HIV-1) infection. The mechanism of this process remains mysterious owing to the NPC complexity and the labyrinth of molecular interactions involved. Here we built a suite of NPC mimics-DNA-origami-corralled nucleoporins with programmable arrangements-to model HIV-1 nuclear entry. Using this system, we determined that multiple cytoplasm-facing Nup358 molecules provide avid binding for capsid docking to the NPC. The nucleoplasm-facing Nup153 preferentially attaches to high-curvature regions of the capsid, positioning it for tip-leading NPC insertion. Differential capsid binding strengths of Nup358 and Nup153 constitute an affinity gradient that drives capsid penetration. Nup62 in the NPC central channel forms a barrier that viruses must overcome during nuclear import. Our study thus provides a wealth of mechanistic insight and a transformative toolset for elucidating how viruses like HIV-1 enter the nucleus.

DOI: https://doi.org/10.1038/s41594-023-00925-9

Acta Pharmacol Sin. 2023 Feb 20.

Downregulation of NUP93 aggravates hypoxia-induced death of cardiomyocytes in vitro through abnormal regulation of gene transcription.

Lei Pan, Xiao-Wei Song, Jin-Chao Song, Cheng-Yong Shi, Zhong-Kai Wang, Song-Qun Huang, Zhi-Fu Guo, Song-Hua Li, Xian-Xian Zhao, Jun-Bo Ge.

Nuclear pore complex in the nuclear envelope plays an important role in controlling the transportation of RNAs, proteins and other macromolecules between the nucleus and cytoplasm. The relationship between abnormal expression of nucleoporins and cardiovascular diseases is unclear. In this study we investigated how myocardial infarction affected the expression and function of nucleoporins in cardiomyocytes. We separately knocked down 27 nucleoporins in rat primary myocardial cells. Among 27 nucleoporins, knockdown of Nup93, Nup210 and Nup214 markedly increased the expression of ANP and BNP, two molecular markers of cardiomyocyte function. We showed that Nup93 was significantly downregulated in hypoxic cardiomyocytes. Knockdown of Nup93 aggravated hypoxia-induced injury and cell death of cardiomyocytes, whereas overexpression of Nup93 led to the opposite effects. RNA-seq and bioinformatics analysis revealed that knockdown of Nup93 did not affect the overall transportation of mRNAs from the nucleus to the cytoplasm, but regulated the transcription of a large number of mRNAs in cardiomyocytes, which are mainly involved in oxidative phosphorylation and ribosome subunits. Most of the down-regulated genes by Nup93 knockdown overlapped with the genes whose promoters could be directly bound by Nup93. Among these genes, we demonstrated that Nup93 knockdown significantly down-regulated the expression of YAP1. Overexpression of YAP1 partially rescued the function of Nup93 knockdown and attenuated the effects of hypoxia on cell injury and cardiomyocyte death. We conclude that down-regulation of Nup93, at least partially, contributes to hypoxia-induced injury and cardiomyocyte death through abnormal interaction with the genome to dynamically regulate the transcription of YAP1 and other genes. These results reveal a new mechanism of Nup93 and might provide new therapeutic targets for the treatment of ischemia-induced heart failure.

Keywords: NUP93; YAP1; hypoxia; myocardial infarction; nuclear pore complex; transcription

DOI: https://doi.org/10.1038/s41401-022-01036-9