title: The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.
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.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yuki
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Abe
authors.affiliation: Department of Computer Science, Graduate School of Information Science and Technology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tamada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Homma
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tagawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004330:Drosophila / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D000071058:Huntingtin Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007814:Larva / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011679:Pupa / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000546:Amanitins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D000071058:Huntingtin Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D044844:beta-Transducin Repeat-Containing Proteins; D000097869:Polo-Like Kinase 1; C121363:Hnrnpab protein, rat; C542005:Htt protein, Drosophila