Double-stranded RNA and/or heat-shock as initiators of chaperone mode switches in diseases associated with protein aggregation?
Donald R. Forsdyke, Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada K7L3N6. Cell Stress & Chaperones (2000) 5, 375-6
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Diseases associated with protein aggregates (e.g. trinucleotide repeat diseases, prion diseases) may help us understand the role of protein aggregation and chaperones in these intracellular self/not-self discriminations (leading to detection and elimination of a cell with foreign nucleic acid or with a mutated oncogene; Forsdyke 1995, 1999).
There is growing evidence that foreign (not-self) nucleic acid, by way of double-stranded RNA (dsRNA), can trigger post-transcriptional gene silencing (Fire 1999), which can be temperature-dependent (Fortier and Belote 2000). Consistent with this, self-RNAs are "purine loaded" thus preventing inadvertent formation of self-dsRNA, an adaptation which is particularly apparent in thermophiles (Lao and Forsdyke 2000).
dsRNA can trigger a protein kinase (PKR) and upregulate expression of various interferon and MHC protein genes. Trinucleotide repeats can form dsRNA hairpins, which also activate PKR (Tian et al. 2000).
If some disease features were the result of intracellular alarms triggered by dsRNA, this would explain the difficulty of correlating these features with protein aggregation. Formation of a sufficient length of dsRNA might lead to cell death either by apoptosis, or by switch of molecular chaperones from protein-disaggregation mode to protease + peptide-presentation mode, allowing cytotoxic T-cell recognition of MHC-peptide complexes (Forsdyke 1999).
There are repeats in human and yeast prion-precursor genes, whose RNAs can adopt dsRNA structures (Poisson and Barrette 2000), but it is not known if these can activate PKR. Some prion diseases require both internal prion-precursor genes and exogenous agents (Hunter et al. 1997). These agents might induce pyrexia and/or activate PKR resulting in chaperone-mode switching for presentation of peptides from prion aggregates.
The mode switch might be evident as a change from one type of chaperone (e.g. constitutive hsp70) to another (e.g. inducible hsp70; Menoret et al. 1995). Intriguingly, in bacteria a single protein has the capacity to switch from chaperone mode to proteolytic mode as temperature increases (Spiess et al. 1999).
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Fortier E and Belote JM (2000) Temperature-dependent gene silencing by an expressed inverted repeat in Drosophila. Genesis 26: 240-244.
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Lao PJ and Forsdyke DR (2000) Thermophilic bacteria strictly obey Szybalski’s transcription direction rule and politely purine-load RNAs with both adenine and guanine. Genome Res. 10, 228-236
Ménoret A Patry Y Burg C Le Pendu J (1995) Co-segregation of tumor immunogenicity with expression of inducible but not constitutive hsp70 in rat colon carcinomas. J. Immunol. 155: 740-747.
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Spiess C, Bell A, Ehrmann M (1999) A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97: 339-347.
Tian B, White RJ, Xia T, Welle S, Turner DH, Mathews MB and Thornton CA (2000) Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6, 79-87.
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Last edited 02 August 2003 by Donald Forsdyke