Higurashi Takashi, Hines Justin K, Sahi Chandan, Aron Rebecca, Craig Elizabeth A
Department of Biochemistry, University of Wisconsin, 445 Biochemistry Addition, 433 Babcock Drive, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16596-601. doi: 10.1073/pnas.0808934105. Epub 2008 Oct 27.
Yeast prions, such as [PSI(+)], [RNQ(+)], and [URE3], are heritable elements formed by proteins capable of acquiring self-perpetuating conformations. Their propagation is dependent on fragmentation of the amyloid protein complexes formed to generate the additional seeds necessary for conversion of nascent soluble protein to the prion conformation. We report that, in addition to its known role in [RNQ(+)] propagation, Sis1, a J-protein cochaperone of Hsp70 Ssa, is also specifically required for propagation of [PSI(+)] and [URE3]. Whereas both [RNQ(+)] and [URE3] are cured rapidly upon SIS1 repression, [PSI(+)] loss is markedly slower. This disparity cannot be explained simply by differences in seed number, as [RNQ(+)] and [PSI(+)] are lost with similar kinetics upon inhibition of Hsp104, a remodeling protein required for propagation of all yeast prions. Rather, in the case of [PSI(+)], our results are consistent with the partial impairment, rather than the complete abolition, of fragmentation of prion complexes upon Sis1 depletion. We suggest that a common set of molecular chaperones, the J-protein Sis1, the Hsp70 Ssa, and the AAA+ ATPase Hsp104, act sequentially in the fragmentation of all yeast prions, but that the threshold of Sis1 activity required for each prion varies.
酵母朊病毒，如[PSI(+)]、[RNQ(+)]和[URE3]，是由能够获得自我延续构象的蛋白质形成的可遗传元件。它们的传播依赖于形成的淀粉样蛋白复合物的片段化，以产生将新生可溶性蛋白转化为朊病毒构象所需的额外种子。我们报告称，除了其在[RNQ(+)]传播中已知的作用外，Hsp70 Ssa的J蛋白共伴侣Sis1也是[PSI(+)]和[URE3]传播所特别需要的。虽然在SIS1抑制后[RNQ(+)]和[URE3]都能迅速消除，但[PSI(+)]的丧失明显较慢。这种差异不能简单地用种子数量的差异来解释，因为在抑制Hsp104（所有酵母朊病毒传播所需的重塑蛋白）后，[RNQ(+)]和[PSI(+)]以相似的动力学丧失。相反，就[PSI(+)]而言，我们的结果与Sis1缺失时朊病毒复合物片段化的部分受损而非完全消除一致。我们认为，一组共同的分子伴侣，即J蛋白Sis1、Hsp70 Ssa和AAA+ ATP酶Hsp104，在所有酵母朊病毒的片段化过程中依次起作用，但每种朊病毒所需的Sis1活性阈值各不相同。
