Article
Biochemistry & Molecular Biology
Kei Higuchi, Koki Sugiyama, Ryuto Tomabechi, Hisanao Kishimoto, Katsuhisa Inoue
Summary: Monocarboxylate transporter 7 (MCT7) is a transporter expressed in the liver, brain, and several types of cancer cells. It has been reported to be a survival factor in melanoma and breast cancers. This study reveals that MCT7 may function as a low-affinity facilitative taurine transporter and its interaction with ancillary proteins enhances taurine transport.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemical Research Methods
Giada Forlani, Enoch B. Antwi, Daniel Weis, Mehmet A. Oeztuerk, Bastian A. W. Queck, Dominik Brecht, Barbara Di Ventura
Summary: The LEXY optogenetic tool with mutated LOV variants showed improved depletion of certain POIs from the nucleus in Drosophila embryos. However, when tested in mammalian cells, these variants led to increased cytoplasmic localization of proteins both after illumination and during dark phases, indicating higher system leakiness.
ACS SYNTHETIC BIOLOGY
(2022)
Article
Biochemical Research Methods
Giada Forlani, Enoch B. Antwi, Daniel Weis, Mehmet A. Oeztuerk, Bastian A. W. Queck, Dominik Brecht, Barbara Di Ventura
Summary: LEXY is an optogenetic tool that exports proteins from the nucleus. Mutations that improve protein depletion from the nucleus and work under low light conditions also increase system leakiness.
ACS SYNTHETIC BIOLOGY
(2022)
Article
Biochemical Research Methods
Stefanie Muhlhausen, Laurence D. Hurst
Summary: Transgene-design is a web application that assists in designing transgenes for mammalian studies. It utilizes the discovery that transgenes without introns and native retrogenes can be highly expressed if the GC content at exonic synonymous sites is high. The application allows for the manipulation of exonic splice enhancers and the option to retain the first intron and protect or avoid specific motifs.
Article
Cell Biology
Yael Udi, Wenzhu Zhang, Milana E. E. Stein, Inna Ricardo-Lax, Hilda A. A. Pasolli, Brian T. T. Chait, Michael P. P. Rout
Summary: Subcellular fractionation combined with mass spectrometry-based proteomics is a powerful tool for studying protein localization in health and disease. We have provided a reliable and fast method for mammalian cell fractionation, specifically designed for proteomic analysis. This method can be applied to different cell lines, maintaining the integrity of the nucleus and nuclear envelope, and accounting for all cellular contents. We demonstrated the utility of this method by quantifying the effects of a nuclear export inhibitor on nucleoplasmic and cytoplasmic proteomes.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Virology
Clifton L. Ricana, Marc C. Johnson
Summary: This study describes a nuclear cycling-deficient RSV Gag mutant with similar plasma membrane binding and genome incorporation to wild-type virus, suggesting that RSV Gag nuclear cycling is not strictly required for RSV replication. This mutant provides insights into viral trafficking evolution and may present a model intermediate to cis- and trans-acting mechanisms for gRNA export.
JOURNAL OF VIROLOGY
(2021)
Article
Multidisciplinary Sciences
Ke Zhang, Lisa Miorin, Tadashi Makio, Ishmael Dehghan, Shengyan Gao, Yihu Xie, Hualin Zhong, Matthew Esparza, Thomas Kehrer, Anil Kumar, Tom C. Hobman, Christopher Ptak, Boning Gao, John D. Minna, Zhijian Chen, Adolfo Garcia-Sastre, Yi Ren, Richard W. Wozniak, Beatriz M. A. Fontoura
Summary: The research shows that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, leading to retention of cellular mRNAs in the nucleus during infection. Increasing levels of NXF1 can rescue the Nsp1-mediated mRNA export block and inhibit SARS-CoV-2 infection. Antagonizing the inhibitory function of Nsp1 on mRNA export may represent a strategy to restore proper antiviral host gene expression in infected cells.
Article
Biochemistry & Molecular Biology
Zheyuan Shen, Weihao Zhuang, Kang Li, Yu Guo, Bingxue Qu, Sikang Chen, Jian Gao, Jing Liu, Lei Xu, Xiaowu Dong, Jinxin Che, Qimeng Li
Summary: This study develops a hybrid virtual screening workflow for XPO1 covalent inhibitor screening. Several promising molecules were obtained, among which compound 8 showed good performance in both tumor cell proliferation assays and nuclear export inhibition assays. Molecular dynamics simulations provided insights into the interaction between compound 8 and XPO1.
Article
Hematology
Maria Paola Martelli, Roberta Rossi, Alessandra Venanzi, Manja Meggendorfer, Vincenzo Maria Perriello, Giovanni Martino, Orietta Spinelli, Raffaella Ciurnelli, Emanuela Varasano, Lorenzo Brunetti, Stefano Ascani, Corinne Quadalti, Valeria Cardinali, Federica Mezzasoma, Ilaria Gionfriddo, Francesca Milano, Roberta Pacini, Alessia Tabarrini, Barbara Bigerna, Francesco Albano, Giorgina Specchia, Calogero Vetro, Francesco Di Raimondo, Ombretta Annibali, Giuseppe Avvisati, Alessandro Rambaldi, Franca Falzetti, Enrico Tiacci, Paolo Sportoletti, Torsten Haferlach, Claudia Haferlach, Brunangelo Falini
Summary: This study identified mutations in Nucleophosmin (NPM1) in acute myeloid leukemia (AML) affecting not only exon 12, but also exons 9, 11, and even exon 5. Novel rearrangements of NPM1 were also discovered. Functional studies showed the importance of cytoplasmic accumulation of NPM1 in leukemogenesis. Additional assays for molecular diagnosis of NPM1-mutated AML are needed.
Article
Microbiology
Sona Vasudevan, James N. Baraniuk
Summary: Nsp1, a virulence factor found in all beta coronaviruses, interacts with the NXF1-NXT1 complex, disrupting normal mRNA transport. Targeting the binding surface between Nsp1 and NXF1-NXT1 with drugs could be a useful strategy to restore host antiviral gene expression in COVID-19 infection. The discovery of repurposed drugs like ganirelix offers potential therapeutic options to block Nsp1 binding and normalize nuclear export.
Review
Microbiology
Tomoko Takahashi, Steven M. Heaton, Nicholas F. Parrish
Summary: Viruses are widespread and organisms have evolved various immune systems to limit virus replication. While protein-guided immune systems in mammals are well studied, small RNA-directed immune systems also play important roles in certain contexts, indicating their continued activity in mammalian antiviral immunity.
Article
Virology
Luis Adrian De Jesus-Gonzalez, Selvin Noe Palacios-Rapalo, Jose Manuel Reyes-Ruiz, Juan Fidel Osuna-Ramos, Carlos Noe Farfan-Morales, Carlos Daniel Cordero-Rivera, Bulmaro Cisneros, Ana Lorena Gutierrez-Escolano, Rosa Maria del Angel
Summary: Recent evidence suggests that nuclear elements play a role in the replication of Flaviviruses, with certain viral proteins being imported into the nucleus. Furthermore, nuclear localization of these proteins has been observed in infected cells. The presence of ZIKV NS3 in the nucleus has been investigated, showing that NS3 is imported into the nucleus via the importin pathway and exported back to the cytoplasm.
JOURNAL OF VIROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ibrahim M. Sabbarini, Dvir Reif, Alexander J. McQuown, Anjali R. Nelliat, Jeffrey Prince, Britnie Santiago Membreno, Colin Chih-Chien Wu, Andrew W. Murray, Vladimir Denic
Summary: The conserved regulon of heat shock factor 1 in budding yeast contains chaperones for general protein folding as well as zinc-finger protein Zpr1, whose essential role in archaea and eukaryotes remains unknown. Here, we show that Zpr1 depletion causes acute proteotoxicity driven by biosynthesis of misfolded eukaryotic translation elongation factor 1A (eEF1A). Prolonged Zpr1 depletion leads to eEF1A insufficiency, thereby inducing the integrated stress response and inhibiting protein synthesis. Strikingly, we show by using two distinct biochemical reconstitution approaches that Zpr1 enables eEF1A to achieve a conformational state resistant to protease digestion. Lastly, we use a ColabFold model of the Zpr1-eEF1A complex to reveal a folding mechanism mediated by the Zpr1's zinc-finger and alpha-helical hairpin structures. Our work uncovers the long-sought-after function of Zpr1 as a bespoke chaperone tailored to the biogenesis of one of the most abundant proteins in the cell.
Article
Plant Sciences
Yuqin Lei, Yuling Li, Yuping Tan, Zhiyong Qian, Qiao Zhou, Da Jia, Qingxiang Sun
Summary: Plant-derived CRM1 inhibitors plumbagin and oridonin inhibit CRM1 activity through multiple mechanisms, including directly targeting the NES groove and promoting CRM1 aggregation. The oridonin complex reveals for the first time a more open NES groove structure. These findings may provide new strategies for the development of CRM1 inhibitors.
JOURNAL OF NATURAL PRODUCTS
(2021)
Article
Microbiology
Fakhar E. Waqas, Mahmoud Shehata, Walid A. M. Elgaher, Antoine Lacour, Naziia B. Kurmasheva, Fabio Begnini, Anders Kiib, Julia Dahlmann, Chutao Chen, Andreas Pavlou, Thomas Poulsen, Sylvia Merkert, Ulrich S. Martin, Ruth Olmer, David S. Olagnier, Anna K. H. Hirsch, Stephan S. Pleschka, Frank Pessler
Summary: Virus infections can cause organ damage through inflammation and oxidative stress. This study evaluated NRF2 activators as potential host-directed treatments for influenza virus infection. The compounds reduced viral replication, inflammation, and reactive oxygen species by interfering with the export of viral RNA/protein complexes, independent of the NRF2 signaling pathway.
Review
Neurosciences
Mireille Khacho, Richard Harris, Ruth S. Slack
NATURE REVIEWS NEUROSCIENCE
(2019)
Article
Cell Biology
Nasim Haghandish, R. Mitchell Baldwin, Alan Morettin, Haben Tesfu Dawit, Hemanta Adhikary, Jean-Yves Masson, Rachid Mazroui, Laura Trinkle-Mulcahy, Jocelyn Cote
MOLECULAR BIOLOGY OF THE CELL
(2019)
Review
Cell Biology
Nicole Baker, Jeel Patel, Mireille Khacho
Review
Cell Biology
Roxanne Oshidari, Karim Mekhail, Andrew Seeber
TRENDS IN CELL BIOLOGY
(2020)
Article
Multidisciplinary Sciences
Roxanne Oshidari, Richard Huang, Maryam Medghalchi, Elizabeth Y. W. Tse, Nasser Ashgriz, Hyun O. Lee, Haley Wyatt, Karim Mekhail
NATURE COMMUNICATIONS
(2020)
Review
Cell Biology
Negin Khosraviani, Lauren A. Ostrowski, Karim Mekhail
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2019)
Article
Multidisciplinary Sciences
Karan J. Abraham, Negin Khosraviani, Janet N. Y. Chan, Aparna Gorthi, Anas Samman, Dorothy Y. Zhao, Miling Wang, Michael Bokros, Elva Vidya, Lauren A. Ostrowski, Roxanne Oshidari, Violena Pietrobon, Parasvi S. Patel, Arash Algouneh, Rajat Singhania, Yupeng Liu, V. Talya Yerlici, Daniel D. De Carvalho, Michael Ohh, Brendan C. Dickson, Razq Hakem, Jack F. Greenblatt, Stephen Lee, Alexander J. R. Bishop, Karim Mekhail
Article
Multidisciplinary Sciences
Lauren A. Todd, Amanda C. Hall, Violena Pietrobon, Janet N. Y. Chan, Guillaume Laflamme, Karim Mekhail
SCIENTIFIC REPORTS
(2020)
Review
Biology
Guillaume Laflamme, Karim Mekhail
COMMUNICATIONS BIOLOGY
(2020)
Article
Medicine, Research & Experimental
Parasvi S. Patel, Karan Joshua Abraham, Kiran Kumar Naidu Guturi, Marie-Jo Halaby, Zahra Khan, Luis Palomero, Brandon Ho, Shili Duan, Jonathan St-Germain, Arash Algouneh, Francesca Mateo, Samah El Ghamrasni, Haithem Barbour, Daniel R. Barnes, Jonathan Beesley, Otto Sanchez, Hal K. Berman, Grant W. Brown, El Bachir Affar, Georgia Chenevix-Trench, Antonis C. Antoniou, Cheryl H. Arrowsmith, Brian Raught, Miquel Angel Pujana, Karim Mekhail, Anne Hakem, Razqallah Hakem
Summary: Germline mutations in BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer, while the loss of RNF168 can protect Brca1-mutant mice against mammary tumorigenesis. Studies have shown that RNF168 deficiency leads to accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, causing cell death.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Review
Cell Biology
Mitra Shokrollahi, Karim Mekhail
Summary: Microtubules play a crucial role in mediating fundamental cellular processes, including cell division, and recent evidence suggests they also regulate the nucleus during the interphase stage of the cell cycle. By exerting cytoplasmic forces on the nucleus, transporting molecular cargo like DNA, and establishing connections with nuclear envelope elements, microtubules impact genome function and organismal health. Overall, the literature indicates that interphase microtubules are critical regulators of nuclear structure and genome stability.
TRENDS IN CELL BIOLOGY
(2021)
Review
Genetics & Heredity
Mia Stanic, Karim Mekhail
Summary: The maintenance of genome stability and cellular homeostasis relies on the coordination of DNA damage response (DDR) with other cellular processes. This review examines the crosstalk between DNA repair factors, chromatin remodeling, replication, transcription, genome organization, cytoskeletal forces, and liquid-liquid phase separation (LLPS) in mediating DNA repair. The authors present an overarching DNA repair framework that incorporates these dynamic processes in the nucleus.
TRENDS IN GENETICS
(2022)
Article
Multidisciplinary Sciences
Yanli Liu, Aman Iqbal, Weiguo Li, Zuyao Ni, Yalong Wang, Jurupula Ramprasad, Karan Joshua Abraham, Mengmeng Zhang, Dorothy Yanling Zhao, Su Qin, Peter Loppnau, Xinghua Guo, Mengqi Zhou, Peter J. Brown, Xuechu Zhen, Guoqiang Xu, Karim Mekhail, Xingyue Ji, Mark T. Bedford, Jack F. Greenblatt, Jinrong Min
Summary: In this study, a potent and selective antagonist targeting the Tudor domain of SMN is reported, which disrupts the interaction between SMN and RNA Polymerase II, mimicking the effects of SMN deficiency.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Parasvi S. Patel, Arash Algouneh, Rehna Krishnan, John J. Reynolds, Kevin C. J. Nixon, Jun Hao, Jihoon Lee, Yue Feng, Chehronai Fozil, Mia Stanic, Talya Yerlici, Peiran Su, Fraser Soares, Elisabeth Liedtke, Gil Prive, Gary D. Baider, Miquel Angel Pujana, Karim Mekhail, Housheng Hansen He, Anne Hakem, Grant S. Stewart, Razqallah Hakem
Summary: BRCA1 mutations increase the risk of breast and ovarian cancer. This study identified MEPCE and PAF1 as synthetic lethal partners of BRCA1 by targeting CRISPR-Cas9 screening. Depletion of MEPCE and PAF1 resulted in dysregulated RNAPII promoter-proximal pausing, R-loop accumulation, replication stress, and genomic instability, leading to the loss of viability in BRCA1-deficient cells. These findings suggest that targeting transcription-replication collision-inducing factors could be a potential therapeutic approach for cancers associated with BRCA1 mutations.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemical Research Methods
Negin Khosraviani, Karan J. Abraham, Janet N. Y. Chan, Karim Mekhail
Summary: This study presents a locus-associated R-loop-modulating system that can attribute functions to R-loops in a locus-specific manner using an inducible RNaseH1-EGFP-dCas9 chimaera. The study confirms the expression, localization, locus-targeted association, and modulation of R-loops in cis or trans using immunoblotting, microscopy, and chromatin and DNA-RNA immunoprecipitation.