bims-nucpor 2022-02-20 papers

bims-nucpor

Biomed News

on Nuclear pore complex and nucleoporins in stress, aging and disease

Issue of 2022–02–20
nine papers selected by
Sara Mingu, Johannes Gutenberg University

Emerging Connections between Nuclear Pore Complex Homeostasis and ALS.
Uip4p modulates nuclear pore complex function in Saccharomyces cerevisiae.
Partial Disassembly of the Nuclear Pore Complex Proteins during Semi-Closed Mitosis in Dictyostelium discoideum.
Generating Membrane Curvature at the Nuclear Pore: A Lipid Point of View.
Cryo-EM structure of the nuclear ring from Xenopus laevis nuclear pore complex.
Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth.
DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity.
A Pan-Cancer Analysis of the Oncogenic Role of Nuclear Transport Factor 2 in Human Cancers.
Distinct Pathologic Feature of Myeloid Neoplasm with t(v;11p15); NUP98 Rearrangement.

Int J Mol Sci. 2022 Jan 25. pii: 1329. [Epub ahead of print]23(3):

Emerging Connections between Nuclear Pore Complex Homeostasis and ALS.

Sunandini Chandra, C Patrick Lusk.

  Developing effective treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) requires understanding of the underlying pathomechanisms that contribute to the motor neuron loss that defines the disease. As it causes the largest fraction of familial ALS cases, considerable effort has focused on hexanucleotide repeat expansions in the C9ORF72 gene, which encode toxic repeat RNA and dipeptide repeat (DPR) proteins. Both the repeat RNA and DPRs interact with and perturb multiple elements of the nuclear transport machinery, including shuttling nuclear transport receptors, the Ran GTPase and the nucleoporin proteins (nups) that build the nuclear pore complex (NPC). Here, we consider recent work that describes changes to the molecular composition of the NPC in C9ORF72 model and patient neurons in the context of quality control mechanisms that function at the nuclear envelope (NE). For example, changes to NPC structure may be caused by the dysregulation of a conserved NE surveillance pathway mediated by the endosomal sorting complexes required for the transport protein, CHMP7. Thus, these studies are introducing NE and NPC quality control pathways as key elements in a pathological cascade that leads to C9ORF72 ALS, opening entirely new experimental avenues and possibilities for targeted therapeutic intervention.

Keywords:  C9ORF72 ALS; CHMP7; ESCRT; NPC injury; POM121; nuclear quality control; nuclear transport

DOI:  https://doi.org/10.3390/ijms23031329
Nucleus. 2022 Dec;13(1): 79-93

Uip4p modulates nuclear pore complex function in Saccharomyces cerevisiae.

Pallavi Deolal, Imlitoshi Jamir, Krishnaveni Mishra.

  A double membrane bilayer perforated by nuclear pore complexes (NPCs) governs the shape of the nucleus, the prominent distinguishing organelle of a eukaryotic cell. Despite the absence of lamins in yeasts, the nuclear morphology is stably maintained and shape changes occur in a regulated fashion. In a quest to identify factors that contribute to regulation of nuclear shape and function in Saccharomyces cerevisiae, we used a fluorescence imaging based approach. Here we report the identification of a novel protein, Uip4p, that is required for regulation of nuclear morphology. Loss of Uip4 compromises NPC function and loss of nuclear envelope (NE) integrity. Our localization studies show that Uip4 localizes to the NE and endoplasmic reticulum (ER) network. Furthermore, we demonstrate that the localization and expression of Uip4 is regulated during growth, which is crucial for NPC distribution.

Keywords:  Nuclear envelope; Uip4; nuclear pore complex; yeast

DOI:  https://doi.org/10.1080/19491034.2022.2034286
Cells. 2022 Jan 25. pii: 407. [Epub ahead of print]11(3):

Partial Disassembly of the Nuclear Pore Complex Proteins during Semi-Closed Mitosis in Dictyostelium discoideum.

Kristina Mitic, Marianne Grafe, Petros Batsios, Irene Meyer.

  Dictyostelium cells undergo a semi-closed mitosis, during which the nuclear envelope (NE) persists; however, free diffusion between the cytoplasm and the nucleus takes place. To permit the formation of the mitotic spindle, the nuclear envelope must be permeabilized in order to allow diffusion of tubulin dimers and spindle assembly factors into the nucleus. In Aspergillus, free diffusion of proteins between the cytoplasm and the nucleus is achieved by a partial disassembly of the nuclear pore complexes (NPCs) prior to spindle assembly. In order to determine whether this is also the case in Dictyostelium, we analysed components of the NPC by immunofluorescence microscopy and live cell imaging and studied their behaviour during interphase and mitosis. We observed that the NPCs are absent from the contact area of the nucleoli and that some nucleoporins also localize to the centrosome and the spindle poles. In addition, we could show that, during mitosis, the central FG protein NUP62, two inner ring components and Gle1 depart from the NPCs, while all other tested NUPs remained at the NE. This leads to the conclusion that indeed a partial disassembly of the NPCs takes place, which contributes to permeabilisation of the NE during semi-closed mitosis.

Keywords:  Dictyostelium; centrosome; nuclear pore complex; nucleoporins; semi-closed mitosis

DOI:  https://doi.org/10.3390/cells11030407
Cells. 2022 Jan 29. pii: 469. [Epub ahead of print]11(3):

Generating Membrane Curvature at the Nuclear Pore: A Lipid Point of View.

Bas W A Peeters, Alexandra C A Piët, Maarten Fornerod.

  In addition to its structural role in enclosing and protecting the genome, the nuclear envelope (NE) forms a highly adaptive communication interface between the cytoplasm and the nuclear interior in eukaryotic cells. The double membrane of the NE is perforated by nuclear pores lined with large multi-protein structures, called nuclear-pore complexes (NPCs), which selectively allow the bi-directional transport of ions and macromolecular cargo. In order to nucleate a pore, the inner and outer nuclear membrane have to fuse at the site of NPC insertion, a process requiring both lipid bilayers to be deformed into highly curved structures. How this curvature is achieved and which factors are involved in inducing and stabilizing membrane curvature at the nuclear pore remain largely unclear. In this review, we will summarize the molecular mechanisms thought to be involved in membrane curvature generation, with a particular emphasis on the role of lipids and lipid metabolism in shaping the nuclear pore membrane.

Keywords:  SMPD4; lipids; membrane curvature; nuclear envelope; nuclear pore complex

DOI:  https://doi.org/10.3390/cells11030469
Cell Res. 2022 Feb 17.

Cryo-EM structure of the nuclear ring from Xenopus laevis nuclear pore complex.

Gaoxingyu Huang, Xiechao Zhan, Chao Zeng, Xuechen Zhu, Ke Liang, Yanyu Zhao, Pan Wang, Qifan Wang, Qiang Zhou, Qinghua Tao, Minhao Liu, Jianlin Lei, Chuangye Yan, Yigong Shi.

Nuclear pore complex (NPC) shuttles cargo across the nuclear envelope. Here we present single-particle cryo-EM structure of the nuclear ring (NR) subunit from Xenopus laevis NPC at an average resolution of 5.6 Å. The NR subunit comprises two 10-membered Y complexes, each with the nucleoporin ELYS closely associating with Nup160 and Nup37 of the long arm. Unlike the cytoplasmic ring (CR) or inner ring (IR), the NR subunit contains only one molecule each of Nup205 and Nup93. Nup205 binds both arms of the Y complexes and interacts with the stem of inner Y complex from the neighboring subunit. Nup93 connects the stems of inner and outer Y complexes within the same NR subunit, and places its N-terminal extended helix into the axial groove of Nup205 from the neighboring subunit. Together with other structural information, we have generated a composite atomic model of the central ring scaffold that includes the NR, IR, and CR. The IR is connected to the two outer rings mainly through Nup155. This model facilitates functional understanding of vertebrate NPC.

DOI: https://doi.org/10.1038/s41422-021-00610-w
Cells. 2022 Jan 18. pii: 317. [Epub ahead of print]11(3):

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth.

Hiroya Kondo, Kenji Mishiro, Yuki Iwashima, Yujia Qiu, Akiko Kobayashi, Keesiang Lim, Takahiro Domoto, Toshinari Minamoto, Kazuma Ogawa, Munetaka Kunishima, Masaharu Hazawa, Richard W Wong.

  Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic "readers" of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

Keywords:  BRD4; CRC; IDR; LLPS; MYC; NPC; NUP210; aminocyclopropenone; cell growth; nuclear size

DOI:  https://doi.org/10.3390/cells11030317
Oncogene. 2022 Feb 12.

DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity.

Bin Chen, Feng Xu, Yang Gao, Guanshuo Hu, Kaili Zhu, Huayi Lu, An Xu, Shaopeng Chen, Lijun Wu, Guoping Zhao.

HIGD1A is an important mitochondrial protein recently shown to have a novel nuclear localization under severe stress. However, whether this protein is also associated with the DNA damage response has rarely been studied. Here, we reported that DSBs-induced the translocation of mitochondrial HIGD1A to the nucleus is dependent on nuclear pore complex (NPCs), which finally promotes HR and radio/chemo-resistance. Importantly, NUP93 and HIGD1A physically interact and the interaction domain with NUP93 is located at residues 46-60 of HIGD1A. Chromatin-enriched HIGD1A can then directly interact with RPA. During the early stages of HR, HIGD1A promotes the loading of RPA to DSBs and activates the DNA damage-dependent chromatin association of RAD9-RAD1-HUS1 complex (9-1-1), which stimulates the ATR-Chk1-dependent G2/M DNA damage checkpoint. After facilitating RPA-ssDNA binding, HIGD1A in turn inhibits abnormal persistence of RPA1 foci by promoting ubiquitination of RPA1 and inducing its eventual proteasomal degradation. In addition, we have identified clinical drug Preveon associated with the HIGD1A-NUP93 interaction domain using a virtual screening approach. This compound directly interacted with HIGD1A, which was verified by NMR, and then inhibited HIGD1A translocation. Collectively, we demonstrate a novel role for HIGD1A in DSBs and provide rationale for using HIGD1A inhibitors as cancer therapeutics.

DOI: https://doi.org/10.1038/s41388-022-02226-9
Front Oncol. 2022 ;12 829389

A Pan-Cancer Analysis of the Oncogenic Role of Nuclear Transport Factor 2 in Human Cancers.

Yu Li, Yongsheng Huang, Shuwei Ren, Xing Xiao, Haotian Cao, Juan He.

  Nuclear transport factor 2 (NUTF2) is a GDP-binding protein that participates in the nucleocytoplasmic transport process. The role of NUTF2 in cancer development is largely unknown and lacks systemic assessment across human cancers. In this study, we performed a pan-cancer analysis of NUTF2 in human cancers. Out of 33 types of cancers, 19 types had significantly different expression of NUTF2 between tumor and normal tissues. Meanwhile, survival analysis showed that NUTF2 could be an independent prognostic factor in several tumor types. Further analysis suggested that the expression of NUTF2 expression was correlated with the infiltration of immune cells, such as CD8+ T cells, effector memory CD4+ T cells, and cancer-associated fibroblasts in kidney renal clear cell carcinoma. Moreover, co-expression analysis showed the positive association between NUTF2 and cell proliferation biomarkers (MKI67and PCNA) and epithelial-mesenchymal transition markers (VIM, TWIST1, SNAI1, SNAI2, FN1, and CDH2), suggesting that NUTF2 plays important roles in regulating cancer proliferation and metastasis. This pan-cancer analysis of NUTF2 provides a systemic understanding of its oncogenic role across different types of cancers.

Keywords:  CAFs; NUTF2; pan-cancer; prognostic; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.3389/fonc.2022.829389
Hum Pathol. 2022 Feb 12. pii: S0046-8177(22)00032-6. [Epub ahead of print]

Distinct Pathologic Feature of Myeloid Neoplasm with t(v;11p15); NUP98 Rearrangement.

Marietya I S Lauw, Zhongxia Qi, Lauren Eversmeyer, Sonam Prakash, Kwun Wah Wen, Jingwei Yu, Sara A Monaghan, Nidhi Aggarwal, Linlin Wang.

  Chromosome rearrangements involving NUP98 at 11p15 are rare but recurring abnormalities in acute myeloid leukemia (AML). Here we described 12 cases of myeloid neoplasms with t(v;11p15); NUP98 rearrangement and characterized their pathologic features. Our patient cohort included 10 adults and 2 children with a median age of 51 years. They were predominantly AML (n=10) including de novo AML, therapy-related AML, chronic myeloid leukemia with myeloid blast crisis, and mixed phenotype acute leukemia, as well as therapy-related myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasm with increased blasts. The blasts shared some common features including pink/red cytoplasmic granules, presence of a perinuclear hof, Auer rods, and occasional bilobed nuclei, mimicking acute promyelocytic leukemia (APML). Flow cytometric studies showed blasts positive for MPO, CD117, CD13 and CD33, with a subset of cases negative for CD34 and/or HLA-DR and a subset of cases expressing monocytic markers. The translocations of 11p15 included t(7;11)(p15;p15), t(2;11)(q11;p15), t(9;11)(p22;p15), t(5;11)(q32;p15), and t(11;12)(p15;q13). Three cases showed cryptic NUP98 rearrangement. These patients showed incomplete response to therapy with median overall survival of 17.5 months, a complete remission rate of 25% following chemotherapy induction and primary refractory disease of 58%. It is clinically important to recognize this group of diseases because the blasts can be misclassified as promyelocytes, and NUP98 rearrangement may be cryptic requiring fluorescence in situ hybridization (FISH) study. This case series highlights that NUP98 rearranged myeloid neoplasms are clinically, morphologically, and cytogenetically distinct and could be considered as a separate entity in the WHO classification defined by cytogenetic abnormality.

Keywords:  NUP98 rearrangement; myeloid neoplasm; t(v;11p15)

DOI:  https://doi.org/10.1016/j.humpath.2022.02.004