1. Academic Validation
  2. Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response

Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response

  • Cell Death Dis. 2017 Dec 12;8(12):3203. doi: 10.1038/s41419-017-0008-5.
Yu-Lung Lin 1 Hong-Chieh Tsai 1 2 3 Pei-Yao Liu 1 Michael Benneyworth 4 Li-Na Wei 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 2 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan, ROC.
  • 3 Department of Neurosurgery, Chang-Gung Memorial Hospital and University, Tao-Yuan, Taiwan, ROC.
  • 4 Departments of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 5 Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA. [email protected].
Abstract

Heat shock response (HSR) is a highly conserved transcriptional program that protects organisms against various stressful conditions. However, the molecular mechanisms modulating HSR, especially the suppression of HSR, is poorly understood. Here, we found that RIP140, a wide-spectrum cofactor of nuclear hormone receptors, acts as a co-repressor of heat shock factor 1 (HSF1) to suppress HSR in healthy neurons. When neurons are stressed such as by heat shock or sodium arsenite (As), cells engage specific proteosome-mediated degradation to reduce RIP140 level, thereby relieving the suppression and activating HSR. RIP140 degradation requires specific Tyr-phosphorylation by Syk that is activated in stressful conditions. Lowering RIP140 level protects hippocampal neurons from As stress, significantly it increases neuron survival and improves spine density. Reducing hippocampal RIP140 in the mouse rescues chronic As-induced spatial learning deficits. This is the first study elucidating RIP140-mediated suppression of HSF1-activated HSR in neurons and brain. Importantly, degradation of RIP140 in stressed neurons relieves this suppression, allowing neurons to efficiently and timely engage HSR programs and recover. Therefore, stimulating RIP140 degradation to activate anti-stress program provides a potential preventive or therapeutic strategy for neurodegeneration diseases.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100872
    99.54%, HSF1 Inhibitor