期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：40
页码：E8402-E8410
DOI：10.1073/pnas.1714361114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The yeast prions [PSI+] and [URE3] are folded in-register parallel β-sheet amyloids of Sup35p and Ure2p, respectively. In a screen for antiprion systems curing [PSI+] without protein overproduction, we detected Siw14p as an antiprion element. An array of genetic tests confirmed that many variants of [PSI+] arising in the absence of Siw14p are cured by restoring normal levels of the protein. Siw14p is a pyrophosphatase specifically cleaving the β phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5), suggesting that increased levels of this or some other inositol polyphosphate favors [PSI+] propagation. In support of this notion, we found that nearly all variants of [PSI+] isolated in a WT strain were lost upon loss of ARG82 , which encodes inositol polyphosphate multikinase. Inactivation of the Arg82p kinase by D131A and K133A mutations (preserving Arg82p’s nonkinase transcription regulation functions) resulted the loss of its ability to support [PSI+] propagation. The loss of [PSI+] in arg82 Δ is independent of Hsp104’s antiprion activity. [PSI+] variants requiring Arg82p could propagate in ipk1 Δ (IP5 kinase), kcs1 Δ (IP6 5-kinase), vip1 Δ (IP6 1-kinase), ddp1 Δ (inositol pyrophosphatase), or kcs1 Δ vip1 Δ mutants but not in ipk1 Δ kcs1 Δ or ddp1 Δ kcs1 Δ double mutants. Thus, nearly all [PSI+] prion variants require inositol poly-/pyrophosphates for their propagation, and at least IP6 or 5PP-IP4 can support [PSI+] propagation.
