The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2α kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

[1]  E. Schuman,et al.  The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition , 2020, eLife.

[2]  F. Biagioni,et al.  Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies , 2020, International journal of molecular sciences.

[3]  Suneil K. Kalia,et al.  Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein , 2020, Acta Neuropathologica Communications.

[4]  F. Fiesel,et al.  Autophagy in Parkinson's disease. , 2020, Journal of molecular biology.

[5]  P. Gannon,et al.  The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration. , 2020, Journal of neuropathology and experimental neurology.

[6]  Mercedes E. Alejandro,et al.  De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation , 2019, bioRxiv.

[7]  D. Philpott,et al.  The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling , 2019, Science.

[8]  C. G. Suresh,et al.  Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex. , 2018, International journal of biological macromolecules.

[9]  D. Philpott,et al.  The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1 , 2018, Molecular and Cellular Biochemistry.

[10]  R. Kaufman,et al.  HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. , 2018, Blood.

[11]  J. Höhfeld,et al.  BAG3-mediated proteostasis at a glance , 2017, Journal of Cell Science.

[12]  Andrew H. Chiang,et al.  Protein Misfolding Diseases. , 2017, Annual review of biochemistry.

[13]  M. Colonna,et al.  Microglia Function in the Central Nervous System During Health and Neurodegeneration. , 2017, Annual review of immunology.

[14]  A. Ciechanover,et al.  Protein Quality Control by Molecular Chaperones in Neurodegeneration , 2017, Front. Neurosci..

[15]  J. Frydman,et al.  Protein misfolding in neurodegenerative diseases: implications and strategies , 2017, Translational Neurodegeneration.

[16]  F. Baas,et al.  Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis , 2016, Glia.

[17]  Mila Ljujic,et al.  The integrated stress response , 2016, EMBO reports.

[18]  G. Hajj,et al.  Translational control by eIF2α in neurons: Beyond the stress response , 2016, Cytoskeleton.

[19]  Masato Miyake,et al.  Integrated stress response of vertebrates is regulated by four eIF2α kinases , 2016, Scientific Reports.

[20]  Matthew P. Anderson,et al.  α‐synuclein pathology accumulates in sacral spinal visceral sensory pathways , 2015, Annals of neurology.

[21]  D. Philpott,et al.  Intracellular Bacterial Pathogens Trigger the Formation of U Small Nuclear RNA Bodies (U Bodies) through Metabolic Stress Induction* , 2015, The Journal of Biological Chemistry.

[22]  P. Moseley,et al.  Heat shock response and autophagy—cooperation and control , 2015, Autophagy.

[23]  Jane-Jane Chen.  Translational control by heme-regulated eIF2&agr; kinase during erythropoiesis , 2014, Current opinion in hematology.

[24]  Suneil K. Kalia,et al.  Ubiquitinylation of α-Synuclein by Carboxyl Terminus Hsp70-Interacting Protein (CHIP) Is Regulated by Bcl-2-Associated Athanogene 5 (BAG5) , 2011, PloS one.

[25]  D. Philpott,et al.  pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling* , 2009, The Journal of Biological Chemistry.

[26]  S. Kimball,et al.  Phosphorylation of eIF2alpha in response to 26S proteasome inhibition is mediated by the haem-regulated inhibitor (HRI) kinase. , 2008, The Biochemical journal.

[27]  Bradley T. Hyman,et al.  Correction: Formation of Toxic Oligomeric α-Synuclein Species in Living Cells , 2008, PLoS ONE.

[28]  Bradley T. Hyman,et al.  Formation of Toxic Oligomeric α-Synuclein Species in Living Cells , 2008, PloS one.

[29]  N. Andrews,et al.  The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. , 2007, The Journal of clinical investigation.

[30]  T. Yao,et al.  HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. , 2007, Genes & development.

[31]  Randal J. Kaufman,et al.  Heme-regulated Inhibitor Kinase-mediated Phosphorylation of Eukaryotic Translation Initiation Factor 2 Inhibits Translation, Induces Stress Granule Formation, and Mediates Survival upon Arsenite Exposure* , 2005, Journal of Biological Chemistry.

[32]  T. Iwatsubo,et al.  Phosphorylated α‐synuclein in normal mouse brain , 2004 .

[33]  T. Iwatsubo,et al.  Phosphorylated alpha-synuclein in normal mouse brain. , 2004, FEBS letters.

[34]  S. Naidu,et al.  eIF2B-related disorders: antenatal onset and involvement of multiple organs. , 2003, American journal of human genetics.

[35]  S. Orkin,et al.  Heme‐regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency , 2001, The EMBO journal.

[36]  Jane-Jane Chen,et al.  Translation Initiation Control by Heme-Regulated Eukaryotic Initiation Factor 2α Kinase in Erythroid Cells under Cytoplasmic Stresses , 2001, Molecular and Cellular Biology.

[37]  N. Grammatikakis,et al.  Hsp90 Regulates p50 cdc37 Function during the Biogenesis of the Active Conformation of the Heme-regulated eIF2α Kinase* , 2001, The Journal of Biological Chemistry.

[38]  Jane-Jane Chen,et al.  Hsp90 Is Obligatory for the Heme-regulated eIF-2α Kinase to Acquire and Maintain an Activable Conformation* , 1997, The Journal of Biological Chemistry.

[39]  I. London,et al.  Regulation of protein synthesis by heme-regulated eIF-2α kinase , 1995 .

[40]  I. London,et al.  Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. , 1995, Trends in biochemical sciences.

[41]  I. London,et al.  Regulation of heme-regulated eIF-2α kinase and its expression in erythroid cells , 1994 .

[42]  I. London,et al.  Regulation of heme-regulated eIF-2 alpha kinase and its expression in erythroid cells. , 1994, Biochimie.

[43]  W. C. Groat,et al.  Vasoactive intestinal polypeptide in visceral afferent pathways to the sacral spinal cord of the cat , 1983, Neuroscience Letters.

[44]  P. Anand,et al.  A VIP-containing system concentrated in the lumbosacral region of human spinal cord , 1983, Nature.

[45]  J. Roppolo,et al.  Parasympathetic preganglionic neurons and visceral primary afferents in monkey sacral spinal cord revealed following application of horseradish peroxidase to pelvic nerve , 1983, The Journal of comparative neurology.

[46]  W. D. de Groat,et al.  The distribution of visceral primary afferents from the pelvic nerve to Lissauer's tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus , 1981, The Journal of comparative neurology.