ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

PKR is a sensor of proteotoxic stress via accumulation of cytoplasmic IL-24 (#163)

Sophia Davidson 1 2 , Chien-Hsiung Yu 1 2 , Annemarie Steiner 1 2 , Frédéric Ebstein 3 , Pawat Laohamonthonkul 1 , Klara Kong 1 , Katja Hrovat Schaale 1 , Paul J Baker 4 , Valentina Jarur-Chamy 5 , Dale J Calleja 1 , Cassandra R Harapas 1 2 , Jacob Mitchell 4 , Niall Geoghegan 1 , Michael Mlodzianoski 1 , Fiona Moghaddas 1 , Katherine R Balka 6 , Adriana Almedia De Jesus 4 , Dominic De Nardo 6 , Benjamin T Kile 7 , Anthony J Sadler 8 , M Cecilia Poli 5 , Elke Krüger 3 , Raphaela Goldbach Mansky 4 , Seth L Masters 1 2
  1. Walter and Eliza Hall Institute, Parkville, VICTORIA, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
  3. University Medicine Greifswald, Institute of Medical Biochemistry and Molecular Biology, Greifswald, Germany
  4. Translational Autoinflammatory Disease Section (TADS), NIAID, National Institutes for Health , Bethesda, Maryland, USA
  5. Immunogenetics and Translational Immunology Program, Facultad de Medicina Universidad del Desarrollo- Clínica Alemana, Santiago, Chile
  6. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  7. Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
  8. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia

Proteasome dysfunction can lead to an autoinflammatory disease associated with elevated type I interferon (IFNαβ) and NF-κB signalling, however the innate immune pathway driving this inflammation is currently unknown. Here, we identify Protein Kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in cells from proteasome-associated autoinflammatory disease (PRAAS) patients. Furthermore, genetic deletion or small molecule inhibition of PKR ameliorated inflammation in these contexts. PKR is a rheostat for proteotoxic stress, its activation triggers phosphorylation of eIF2α which prevents the translation of new proteins, thereby promoting a cell’s return to homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction PKR senses the cytoplasmic accumulation of a known interactor, interleukin 24 (IL-24). Importantly, blocking misfolded IL-24 egress into the cytosol via the endoplasmic reticulum degradation pathway blunted PKR activation and subsequent inflammatory signalling. Cytokines such as IL-24 are normally secreted, therefore cytoplasmic accumulation of IL-24 represents a danger associated molecular pattern for the cell. Thus, we have identified a novel mechanism by which cells sense proteotoxic stress, causing inflammation observed in the disease PRAAS.