Publications by authors named "Weirui Ma"

10 Publications

  • Page 1 of 1

Redox-sensitive CDC-42 clustering promotes wound closure in C. elegans.

Cell Rep 2021 Nov;37(8):110040

Center for Stem Cell and Regenerative Medicine and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang University-University of Edinburgh Institute, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

Tissue damage induces immediate-early signals, activating Rho small GTPases to trigger actin polymerization essential for later wound repair. However, how tissue damage is sensed to activate Rho small GTPases locally remains elusive. Here, we found that wounding the C. elegans epidermis induces rapid relocalization of CDC-42 into plasma membrane-associated clusters, which subsequently recruits WASP/WSP-1 to trigger actin polymerization to close the wound. In addition, wounding induces a local transient increase and subsequent reduction of HO, which negatively regulates the clustering of CDC-42 and wound closure. CDC-42 CAAX motif-mediated prenylation and polybasic region-mediated cation-phospholipid interaction are both required for its clustering. Cysteine residues participate in intermolecular disulfide bonds to reduce membrane association and are required for negative regulation of CDC-42 clustering by HO. Collectively, our findings suggest that HO-regulated fine-tuning of CDC-42 localization can create a distinct biomolecular cluster that facilitates rapid epithelial wound repair after injury.
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http://dx.doi.org/10.1016/j.celrep.2021.110040DOI Listing
November 2021

Natural Product Erianin Inhibits Bladder Cancer Cell Growth by Inducing Ferroptosis via NRF2 Inactivation.

Front Pharmacol 2021 29;12:775506. Epub 2021 Oct 29.

School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China.

Erianin, a natural product derived from , has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. , we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.
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http://dx.doi.org/10.3389/fphar.2021.775506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585785PMC
October 2021

In vivo reconstitution finds multivalent RNA-RNA interactions as drivers of mesh-like condensates.

Elife 2021 Mar 2;10. Epub 2021 Mar 2.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, United States.

Liquid-like condensates have been thought to be sphere-like. Recently, various condensates with filamentous morphology have been observed in cells. One such condensate is the TIS granule network that shares a large surface area with the rough endoplasmic reticulum and is important for membrane protein trafficking. It has been unclear how condensates with mesh-like shapes but dynamic protein components are formed. In vitro and in vivo reconstitution experiments revealed that the minimal components are a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions. mRNAs with large unstructured regions have a high propensity to form a pervasive intermolecular interaction network that acts as condensate skeleton. The underlying RNA matrix prevents full fusion of spherical liquid-like condensates, thus driving the formation of irregularly shaped membraneless organelles. The resulting large surface area may promote interactions at the condensate surface and at the interface with other organelles.
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http://dx.doi.org/10.7554/eLife.64252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968931PMC
March 2021

The Role of DNA Methylation Reprogramming during Sex Determination and Transition in Zebrafish.

Genomics Proteomics Bioinformatics 2021 02 19;19(1):48-63. Epub 2021 Feb 19.

CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China. Electronic address:

DNA methylation is a prevalent epigenetic modification in vertebrates, and it has been shown to be involved the regulation of gene expression and embryo development. However, it remains unclear how DNA methylation regulates sexual development, especially in species without sex chromosomes. To determine this, we utilized zebrafish to investigate DNA methylation reprogramming during juvenile germ cell development and adult female-to-male sex transition. We reveal that primordial germ cells (PGCs) undergo significant DNA methylation reprogramming during germ cell development, and the methylome of PGCs is reset to an oocyte/ovary-like pattern at 9 days post fertilization (9 dpf). When DNA methyltransferase (DNMT) activity in juveniles was blocked after 9 dpf, the zebrafish developed into females. We also show that Tet3 is involved in PGC development. Notably, we find that DNA methylome reprogramming during adult zebrafish sex transition is similar to the reprogramming during the sex differentiation from 9 dpf PGCs to sperm. Furthermore, inhibiting DNMT activity can prevent the female-to-male sex transition, suggesting that methylation reprogramming is required for zebrafish sex transition. In summary, DNA methylation plays important roles in zebrafish germ cell development and sexual plasticity.
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http://dx.doi.org/10.1016/j.gpb.2020.10.004DOI Listing
February 2021

Baicalin Induces Apoptosis and Suppresses the Cell Cycle Progression of Lung Cancer Cells Through Downregulating Akt/mTOR Signaling Pathway.

Front Mol Biosci 2020 28;7:602282. Epub 2021 Jan 28.

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Baicalin, as a natural active ingredient extracted and isolated from the traditional Chinese medicine Georgi., has been potentially used in various areas for its antioxidative, antitumor, anti-inflammatory, and anti-proliferative activities. Although several studies have reported the antitumor effects of baicalin against various cancer types, its beneficial effects on lung cancer have not yet been elucidated. Therefore, the therapeutic effects and molecular mechanisms of baicalin on lung cancer cell lines H1299 and H1650 were investigated. Here, the results of its antitumor activity were shown. We found that Akt/mTOR pathway inhibition was the essential determinant in baicalin-induced cell cycle arrest. Furthermore, when the Akt Agonist SC79 or Akt plasmid transfection was performed, the antitumor effect of baicalin was significantly abrogated in both H1299 and H1650 cells. In conclusion, we found that baicalin exerted its antitumor activity mainly by inducing Akt-dependent cell cycle arrest and promoting apoptosis, which show great potential for developing a new drug for lung cancer treatment.
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http://dx.doi.org/10.3389/fmolb.2020.602282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876332PMC
January 2021

A Membraneless Organelle Associated with the Endoplasmic Reticulum Enables 3'UTR-Mediated Protein-Protein Interactions.

Cell 2018 11 15;175(6):1492-1506.e19. Epub 2018 Nov 15.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Approximately half of human genes generate mRNAs with alternative 3' untranslated regions (3'UTRs). Through 3'UTR-mediated protein-protein interactions, alternative 3'UTRs enable multi-functionality of proteins with identical amino acid sequence. While studying how information on protein features is transferred from 3'UTRs to proteins, we discovered that the broadly expressed RNA-binding protein TIS11B forms a membraneless organelle, called TIS granule, that enriches membrane protein-encoding mRNAs with multiple AU-rich elements. TIS granules form a reticular meshwork intertwined with the endoplasmic reticulum (ER). The association between TIS granules and the ER creates a subcellular compartment-the TIGER domain-with a biophysically and biochemically distinct environment from the cytoplasm. This compartment promotes 3'UTR-mediated interaction of SET with membrane proteins, thus allowing increased surface expression and functional diversity of proteins, including CD47 and PD-L1. The TIGER domain is a subcellular compartment that enables formation of specific and functionally relevant protein-protein interactions that cannot be established outside.
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http://dx.doi.org/10.1016/j.cell.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711188PMC
November 2018

Translation repression by maternal RNA binding protein Zar1 is essential for early oogenesis in zebrafish.

Development 2017 01 2;144(1):128-138. Epub 2016 Dec 2.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

A large amount of maternal RNA is deposited in oocytes and is reserved for later development. Control of maternal RNA translation during oocyte maturation has been extensively investigated and its regulatory mechanisms are well documented. However, translational regulation of maternal RNA in early oogenesis is largely unexplored. In this study, we generated zebrafish zar1 mutants that result in early oocyte apoptosis and fully penetrant male development. Loss of p53 suppresses the apoptosis in zar1 mutants and restores oocyte development. zar1 immature ovaries show upregulation of proteins implicated in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). More importantly, loss of Zar1 causes marked upregulation of zona pellucida (ZP) family proteins, while overexpression of ZP proteins in oocytes causes upregulation of stress-related activating transcription factor 3 (atf3), arguing that tightly controlled translation of ZP proteins is essential for ER homeostasis during early oogenesis. Furthermore, Zar1 binds to ZP gene mRNAs and represses their translation. Together, our results indicate that regulation of translational repression and de-repression are essential for precisely controlling protein expression during early oogenesis.
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http://dx.doi.org/10.1242/dev.144642DOI Listing
January 2017

Involvement of Protein Acyltransferase ZDHHC3 in Maintaining Oocyte Meiotic Arrest in Xenopus laevis.

Biol Reprod 2016 Sep 10;95(3):67. Epub 2016 Aug 10.

State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China

Fully grown oocytes of most vertebrates are arrested at prophase I of meiosis (G2 arrest). Upon exposure to steroid hormones, oocytes resume meiotic process, also called G2/M transition. The G protein-signaling pathway has been shown to play essential roles in the meiotic arrest at G2 phase. Previously, we showed that long chain fatty acyl-coenzyme A synthetase acsl1b was required for maintaining the meiotic arrest in Xenopus Acsl1b presumably synthesizes palmitoyl-coenzyme A that can be utilized by acyltransferases to modify proteins essential for the G2 arrest. In the present study, we report that protein acyltransferase ZDHHC3 functions downstream of acsl1b to maintain oocyte meiotic arrest. Depletion of maternal ZDHHC3 RNA in oocytes reduces the progesterone threshold to promote G2/M transition from 2 to 0.01 μM. As expected, G alpha palmitoylation level is greatly decreased in ZDHHC3-depleted oocytes. Furthermore, we mapped ZDHHC3 palmitoylation sites in G alpha and showed that palmitoylation-deficient G alpha failed to arrest oocytes at G2. We also identified a critical residue in ZDHHC3 critically required for its palmitoylation activity toward G alpha. Taken together, ZDHHC3 is a key acyltransferase to palmitoylate proteins in order to maintain G2 arrest in Xenopus oocytes.
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http://dx.doi.org/10.1095/biolreprod.116.138941DOI Listing
September 2016

The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development.

FEBS Lett 2016 07 27;590(14):2076-85. Epub 2016 Jun 27.

State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.

The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy.
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http://dx.doi.org/10.1002/1873-3468.12237DOI Listing
July 2016

Prdm14 acts upstream of islet2 transcription to regulate axon growth of primary motoneurons in zebrafish.

Development 2012 Dec 7;139(24):4591-600. Epub 2012 Nov 7.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

The precise formation of three-dimensional motor circuits is essential for movement control. Within these circuits, motoneurons (MNs) are specified from spinal progenitors by dorsoventral signals and distinct transcriptional programs. Different MN subpopulations have stereotypic cell body positions and show specific spatial axon trajectories. Our knowledge of MN axon outgrowth remains incomplete. Here, we report a zebrafish gene-trap mutant, short lightning (slg), in which prdm14 expression is disrupted. slg mutant embryos show shortened axons in caudal primary (CaP) MNs resulting in defective embryonic movement. Both the CaP neuronal defects and behavior abnormality of the mutants can be phenocopied by injection of a prdm14 morpholino into wild-type embryos. By removing a copy of the inserted transposon from homozygous mutants, prdm14 expression and normal embryonic movement were restored, confirming that loss of prdm14 expression accounts for the observed defects. Mechanistically, Prdm14 protein binds to the promoter region of islet2, a known transcription factor required for CaP development. Notably, disruption of islet2 function caused similar CaP axon outgrowth defects as observed in slg mutant embryos. Furthermore, overexpression of islet2 in slg mutant embryos rescued the shortened CaP axon phenotypes. Together, these data reveal that prdm14 regulates CaP axon outgrowth through activation of islet2 expression.
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http://dx.doi.org/10.1242/dev.083055DOI Listing
December 2012
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