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The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing

Y Mao1, T Tamura1, Y Yuki1

  • 1Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Cell Death & Disease
|April 29, 2016
PubMed

Insights

This study reveals a signaling network for necrotic cell death triggered by transcriptional repression (TRIAD) using α-amanitin (AMA). The hnRNP-Htt axis plays a key role in this process, impacting RNA splicing and cell death.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neurodegenerative diseases involve cell death pathways.
  • Transcriptional repression can induce necrotic cell death.

Purpose of the Study:

  • To identify the signaling network of necrotic cell death induced by transcriptional repression (TRIAD).
  • To investigate the role of heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt) in TRIAD.

Main Methods:

  • Genetic screening of a knockdown fly library.
  • Systems biology analysis of protein-protein interaction networks.
  • RNA sequencing to analyze gene expression and splicing.
  • Fly genetics to validate gene function.

Main Results:

  • Identified a TRIAD signaling network involving hnRNPs and Htt.
  • AMA impaired transcription and RNA splicing of Htt.
  • Overexpression of hnRNP rescued AMA-induced defects.
  • Modulating Htt and hnRNP levels affected cell death.

Conclusions:

  • The hnRNP-Htt axis is involved in TRIAD.
  • RNA splicing plays a critical role in transcriptional repression-induced necrosis.
  • This study provides insights into neurodegenerative cell death mechanisms.

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