Unfolded Protein Response

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Structure of the enzyme Ire1 , a central regulator of the unfolded protein response

When unfolded protein response ( UPR , dt. Unfolded protein response or response to unfolded proteins ) is in the Biology a complex reaction of cells to stress Denoted by the accumulation of proteins with incorrect folding in the endoplasmic reticulum occurs (ER).

The aim of the UPR is to restore normal cell function through the selective suppression of translation processes , through the breakdown of incorrectly folded proteins and through the activation of signaling pathways for the increased synthesis of chaperones , which are necessary for correct protein folding. If these reactions are not effective within a certain time or if the stressful situation persists, the UPR leads to programmed cell death through apoptosis . The protein kinases Ire1 (Inositol-requiring Enzyme 1) and PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase) as well as the transcription factor ATF6 (Activating Transcription Factor 6) play a central role in the regulation of UPR . These three proteins act as sensors that recognize ER stress due to incorrect protein folding and control the functions of the UPR via various signal chains.

From an evolutionary point of view, the UPR is a highly conserved part of protein quality control that is pronounced in the cells of all eukaryotes . It was first described in 1988 by Joseph Sambrook and his wife Mary-Jane Gething at the Southwestern Medical Center of the University of Texas . UPR disorders may play a role in various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease , in metabolic disorders such as diabetes mellitus and obesity, and in cancer .

In addition to the UPR in the ER , an independent "unfolded protein response" has been described in mitochondria (mtUPR). The characterization took place mainly in the nematode C. elegans , but many of the components are conserved and also active in the human system. The mtUPR is triggered by mitochondrial dysfunction and protects the cell through metabolic adaptation and mitochondrial biogenesis. A disturbed mtUPR is associated with age-associated diseases.

literature

  • Claudio Hetz: The unfolded protein response: controlling cell fate decisions under ER stress and beyond. In: Nature Reviews. Molecular Cell Biology. Volume 13, Number 2, February 2012, pp. 89-102, doi : 10.1038 / nrm3270 . PMID 22251901 . (Review).
  • Richard Jäger, Mathieu JM Bertrand, Adrienne M. Gorman, Peter Vandenabeele, Afshin Samali: The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. In: Biology of the Cell. Volume 104, number 5, May 2012, pp. 259-270, doi : 10.1111 / boc.201100055 . PMID 22268789 . (Review).

Individual evidence

  1. ↑ Yasunori Kozutsumi, Mark Segal, Karl Normington, Mary-Jane Gething, Joe Sambrook: The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins . In: Nature . tape 332 , no. 6163 , March 1988, ISSN  0028-0836 , p. 462-464 , doi : 10.1038 / 332462a0 .
  2. ↑ a b Tomer Shpilka, Cole M. Haynes: The mitochondrial UPR: mechanisms, physiological functions and implications in aging . In: Nature Reviews Molecular Cell Biology . tape 19 , no. 2 , February 2018, ISSN  1471-0072 , p. 109–120 , doi : 10.1038 / nrm.2017.110 .
  3. ↑ Mark W. Pellegrino, Amrita M. Nargund, Natalia V. Kirienko, Reba Gillis, Christopher J. Fiorese: Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection . In: Nature . tape 516 , no. 7531 , December 2014, ISSN  0028-0836 , p. 414-417 , doi : 10.1038 / nature13818 , PMID 25274306 , PMC 4270954 (free full text).