RRC ID 40033
著者 Mao Y, Tamura T, Yuki Y, Abe D, Tamada Y, Imoto S, Tanaka H, Homma H, Tagawa K, Miyano S, Okazawa H.
タイトル The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.
ジャーナル Cell Death Dis
Abstract In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis.
巻・号 7(4)
ページ e2207
公開日 2016-4-28
DOI 10.1038/cddis.2016.101
PII cddis2016101
PMID 27124581
PMC PMC4855646
MeSH Amanitins / pharmacology Animals Apoptosis* / drug effects Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cells, Cultured Drosophila / growth & development Drosophila / metabolism Drosophila Proteins / genetics Drosophila Proteins / metabolism* Embryo, Mammalian / cytology Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism Heterogeneous-Nuclear Ribonucleoproteins / genetics Heterogeneous-Nuclear Ribonucleoproteins / metabolism* Huntingtin Protein / antagonists & inhibitors Huntingtin Protein / genetics Huntingtin Protein / metabolism* Larva / metabolism Neurons / cytology Neurons / metabolism Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Pupa / metabolism RNA Splicing / drug effects Rats Rats, Wistar Ribonucleoproteins / genetics Ribonucleoproteins / metabolism Transcription Factors / genetics Transcription Factors / metabolism Transcription, Genetic / drug effects beta-Transducin Repeat-Containing Proteins / genetics beta-Transducin Repeat-Containing Proteins / metabolism
IF 6.304
引用数 7
WOS 分野 CELL BIOLOGY
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