Role of asymmetric segregation and the ribosome associated complex in prion formation and propagation

Prion;Yeast;Ribosome;Ssb;Sir2

Howie, Rebecca Leigh ; Chernoff, Yury O. Biology Lobachev, Kirill Storici, Francesca Ratcliff, William Qin, Hong ; Chernoff, Yury O.

University:Georgia Institute of Technology

Department:Biology

关键词: Prion;    Yeast;    Ribosome;    Ssb;    Sir2;   

Others  :  https://smartech.gatech.edu/bitstream/1853/61163/1/HOWIE-DISSERTATION-2018.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

Self-perpetuating transmissible protein aggregates—prions—are implicated in mammalian diseases and control phenotypically detectable traits in yeast. Yeast heat shock-induced chaperone proteins counteract stress-induced aggregation but also control prion propagation. Heat-damaged proteins that are not disaggregated by chaperones are cleared from daughter cells via mother-specific asymmetric segregation in cell divisions following heat shock. Heat shock-mediated destabilization of [PSI+], a prion isoform of the yeast translation termination factor Sup35, was previously shown to coincide with the imbalance between the Hsp104 and Ssa chaperones. The ribosome associated complex chaperone Ssb has previously been shown to antagonize the function of Ssa in prion propagation. The objective of this work was to better understand prion curing and formation in yeast, and specifically to understand the roles of asymmetric segregation and the ribosome associated complex. We show that cells lacking Sir2, which is responsible for asymmetric segregation of heat-damaged proteins, are impaired in the heat shock-mediated destabilization of [PSI+], and that Sup35 aggregates co-localize with aggregates of heat-damaged proteins. These results support the role of asymmetric segregation in prion destabilization. We then show that depletion of Ssb decreases heat shock-mediated destabilization of [PSI+], while disruption of a co-chaperone complex mediating the binding of Ssb to the ribosome increases prion loss. Ssb is shown to relocate from the ribosome to the cytosol during heat stress. These data support the role of Ssb, a stress non-inducible protein, in prion curing during stress and further implicate chaperone imbalance in prion curing. Lastly, we demonstrate that increased aggregation due to disruption of Ssb or the ribosome-associated complex increases formation of various prions, especially during stress, establishing these as anti-prion components that are necessary for both curing and protection against prion formation.