title: Components of a mammalian protein disaggregation/refolding machine are targeted to nuclear speckles following thermal stress in differentiated human neuronal cells.
abstract: Heat shock proteins (Hsps) are a set of highly conserved proteins involved in cellular repair and protective mechanisms. They counter protein misfolding and aggregation that are characteristic features of neurodegenerative diseases. Hsps act co-operatively in disaggregation/refolding machines that assemble at sites of protein misfolding and aggregation. Members of the DNAJ (Hsp40) family act as "holdases" that detect and bind misfolded proteins, while members of the HSPA (Hsp70) family act as "foldases" that refold proteins to biologically active states. HSPH1 (Hsp105α) is an important additional member of the mammalian disaggregation/refolding machine that acts as a disaggregase to promote the dissociation of aggregated proteins. Components of a disaggregation/refolding machine were targeted to nuclear speckles after thermal stress in differentiated human neuronal SH-SY5Y cells, namely: HSPA1A (Hsp70-1), DNAJB1 (Hsp40-1), DNAJA1 (Hsp40-4), and HSPH1 (Hsp105α). Nuclear speckles are rich in RNA splicing factors, and heat shock disrupts RNA splicing which recovers after stressful stimuli. Interestingly, constitutively expressed HSPA8 (Hsc70) was also targeted to nuclear speckles after heat shock with elements of a disaggregation/refolding machine. Hence, neurons have the potential to rapidly assemble a disaggregation/refolding machine after cellular stress using constitutively expressed Hsc70 without the time lag needed for synthesis of stress-inducible Hsp70. Constitutive Hsc70 is abundant in neurons in the mammalian brain and has been proposed to play a role in pre-protecting neurons from cellular stress.
authors.affiliation: Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada.
authors.forename: Catherine A S
authors.initials: CA
authors.lastname: Deane
authors.affiliation: Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada. ibrown@utsc.utoronto.ca.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Brown
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D050957:HSP110 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D058849:Protein Refolding; D012326:RNA Splicing; D013696:Temperature; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C107481:DNAJA1 protein, human; C494647:DNAJB1 protein, human; D050883:HSC70 Heat-Shock Proteins; D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; C494371:HSPA8 protein, human; C097205:HSPH1 protein, human; D006360:Heat-Shock Proteins; D014212:Tretinoin
keywords: DNAJA1 (Hsp40–4); DNAJB1 (Hsp40–1); HSPA1A (Hsp70–1); HSPA8 (Hsc70); HSPH1 (Hsp105α); Heat shock proteins; Human neuronal SH-SY5Y cells; Nuclear speckles; RNA splicing