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YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA.

ABSTRACT: Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we show that the posttranscriptional regulator Y-box binding protein 1 (YBX1), a DNA- and RNA-binding protein, acts as an oncogene in medulloblastomas by regulating cellular survival and apoptosis. We observed different cellular responses upon YBX1 knockdown in several medulloblastoma cell lines, with significantly altered transcription and subsequent apoptosis rates. Mechanistically, PAR-CLIP for YBX1 and integration with RNA-Seq data uncovered direct posttranscriptional control of the heterochromatin-associated gene CBX5; upon YBX1 knockdown and subsequent CBX5 mRNA instability, heterochromatin-regulated genes involved in inflammatory response, apoptosis and death receptor signaling were de-repressed. Thus, YBX1 acts as an oncogene in medulloblastoma through indirect transcriptional regulation of inflammatory genes regulating apoptosis and represents a promising novel therapeutic target in this tumor entity.

SUBMITTER: Kloetgen A

PROVIDER: S-EPMC7352269 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA.

Kloetgen Andreas A Duggimpudi Sujitha S Schuschel Konstantin K Hezaveh Kebria K Picard Daniel D Schaal Heiner H Remke Marc M Klusmann Jan-Henning JH Borkhardt Arndt A McHardy Alice C AC Hoell Jessica I JI

International journal of molecular sciences 20200623 12

Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we show that the posttranscriptional regulator Y-box binding protein 1 (YBX1), a DNA- and RNA-binding protein, acts as an oncogene in medulloblastomas by regulating cellular survival and apopto ...[more]

PMID: 32585856

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Project description:Toxoplasma gondii secretes various virulence effector molecules into host cells to disrupt host interferon-γ (IFN-γ)-dependent immunity. Among these effectors, ROP18 directly phosphorylates and inactivates IFN-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), leading to the subversion of IFN-inducible GTPase-induced cell-autonomous immunity. The modes of action of ROP18 have been studied extensively; however, little is known about the molecular mechanisms by which ROP18 is produced in the parasite itself. Here, we report the role of T. gondii transcription factor IWS1 in ROP18 mRNA expression in the parasite. Compared with wild-type virulent type I T. gondii, IWS1-deficient parasites showed dramatically increased loading of IRGs and GBPs onto the parasitophorous vacuole membrane (PVM). Moreover, IWS1-deficient parasites displayed decreased virulence in wild-type mice but retained normal virulence in mice lacking the IFN-γ receptor. Furthermore, IWS1-deficient parasites showed severely decreased ROP18 mRNA expression; however, tagged IWS1 did not directly bind with genomic regions of the ROP18 locus. Ectopic expression of ROP18 in IWS1-deficient parasites restored the decreased loading of effectors onto the PVM and in vivo virulence in wild-type mice. Taken together, these data demonstrate that T. gondii IWS1 indirectly regulates ROP18 mRNA expression to determine fitness in IFN-γ-activated host cells and mice. IMPORTANCE The parasite Toxoplasma gondii has a counterdefense system against interferon-γ (IFN-γ)-dependent host immunity which relies on the secretion of parasite effector proteins. ROP18 is one of the effector, which is released into host cells to inactivate IFN-γ-dependent anti-Toxoplasma host proteins. The mechanism by which Toxoplasma ROP18 subverts host immunity has been extensively analyzed, but how Toxoplasma produces this virulence factor remains unclear. Here, we show that Toxoplasma transcription factor IWS1 is important for ROP18 mRNA expression in the parasite. Loss of IWS1 from virulent Toxoplasma leads to dramatically decreased ROP18 mRNA expression, resulting in profoundly decreased virulence due to greater activity of IFN-γ-dependent host immune responses. Thus, Toxoplasma prepares the critical virulence factor ROP18 via an IWS1-dependent system to negate IFN-γ-dependent antiparasitic immunity and thus survive in the host.

Dataset Information

YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA.

Publications

YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA.

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