Despite decades of scientific research and heightening public and governmental anxiety over the potential dangers of infectious proteins and their role in epidemics such as new variant Creutzfeldt-Jacob disease, Mad Cow disease, and chronic Wasting disease, the mechanisms responsible for the conversion of a normal cellular protein into an infectious prion protein continue to defy understanding. The cellular factors instrumental to the protein conformational changes that result in prion formation, as well as those factors necessary for the subsequent stabilization of the altered prion conformation, remain a mystery. Considering that prion formation and inheritance are tightly related to the protein folding machinery, we propose to investigate the link between prion formation and heat shock transcriptional factors (HSFs). HSFs are evolutionally conserved transcriptional factors responsible for the biosynthesis of the majority of molecular chaperones, which are essential for protecting cells from extreme harsh conditions by refolding or dis-aggregating denatured proteins produced during the stress. Several molecular chaperones are also shown to play essential roles in prion propagation. Using the budding yeast Saccharomyces cerevisiae as the model organism, we propose to elucidate the relationship between HSFs and prion formation/propagation. Our long-term goal of the proposed research is to identify protein factors whose functions are regulated by HSFs and are essential for prion formation/propagation.
The specific aims are: 1) to examine the regulatory role of heat shock protein 90kDa (Hsp90) complex in de novo formation and """"""""strain"""""""" maintenance of [PSI+];2) to test if HSF and Hsp90 complex regulate other yeast prions. We will investigate if the effects of HSF and Hsp90/cochaperones are [PSI+] specific: 3) to identify additional novel factors that are HSF targets and responsible for prion formation and propagation.
Prion diseases are a group of infectious neurodegenerative diseases also known as transmissible spongiform encephalopathies. The molecular mechanisms govern the etiology of prion diseases are poorly understood. We propose to identify cellular factors that are required for prion conformational conversion and are important for subsequent stabilization of the acquired prion conformation. The success of proposed study will likely provide target genes for future drug discovery and new therapeutics for the devastating prion diseases.
|Du, Zhiqiang; Zhang, Ying; Li, Liming (2015) The Yeast Prion [SWI(+)] Abolishes Multicellular Growth by Triggering Conformational Changes of Multiple Regulators Required for Flocculin Gene Expression. Cell Rep 13:2865-78|
|Du, Zhiqiang; Li, Liming (2014) Investigating the interactions of yeast prions: [SWI+], [PSI+], and [PIN+]. Genetics 197:685-700|
|Nussbaum-Krammer, Carmen I; Park, Kyung-Won; Li, Liming et al. (2013) Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans. PLoS Genet 9:e1003351|
|Li, Liming; Kowal, Anthony S (2012) Environmental regulation of prions in yeast. PLoS Pathog 8:e1002973|
|Crow, Emily T; Du, Zhiqiang; Li, Liming (2011) A small, glutamine-free domain propagates the [SWI(+)] prion in budding yeast. Mol Cell Biol 31:3436-44|
|Park, Kyung-Won; Li, Liming (2011) Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology. Prion 5:28-38|
|Crow, Emily T; Li, Liming (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 22:452-9|
|Hines, Justin K; Li, Xiaomo; Du, Zhiqiang et al. (2011) [SWI], the prion formed by the chromatin remodeling factor Swi1, is highly sensitive to alterations in Hsp70 chaperone system activity. PLoS Genet 7:e1001309|
|Fushimi, Kazuo; Long, Charles; Jayaram, Neha et al. (2011) Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein Cell 2:141-9|
|Du, Zhiqiang (2011) The complexity and implications of yeast prion domains. Prion 5:311-6|
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