Accepted postdoctoral position at the Institute for Neurodegenerative Diseases at The University of California, San Francisco after receiving PhD

The Hsp70 class of molecular chaperones play critical roles in protein homeostasis via an ATP-dependent folding cycle. Cytosolic Hsp70s in the budding yeastSaccharomyces cerevisiae,Ssa and Ssb, interact with up to three distinct nucleotide exchange factors (NEFs) homologous to human counterparts; Sse1/Sse2/HSP110, Fes1/HspBP1, and Snl1/Bag-1. In an effort to understand the differential functional contributions of the cytosolic NEFs to protein homeostasis (“proteostasis”), I carried out a comparative genetic, biochemical and cell biological analyses. For these studies, I developed protocols to monitor protein disaggregation and reactivation in a near real-time coupled assay that revealed the importance of aggregate dynamics in solubilization of proteins for refolding. This coupled experimental approach represents an important step toward developing tools necessary to monitor in vivo mechanisms of proteostasis.

这项工作确定Hsp110 Sse1,primary NEF contributing to most Hsp70 functions and uncovered a unique role for Fes1 in Ssa-mediated regulation of the cytosolic heat shock response, while revealing no significant contributions from Snl1 and Sse2. These findings suggest that NEFs do have overlapping functions, but their distinct associations with the Hsp70s as well as unique structural components could contribute to differential roles in proteostasis.

Additionally, this study uncovered that relative levels of Snl1 and Sse1 are important for optimal growth. To probe this relationship, I exploited the Snl1 overexpression toxicity phenotype exhibited in the absence of Sse1 to examine which unique characteristics of Snl1 are important for its function. I discovered that Snl1 localization to the ER membrane was required for toxicity and that Sse1-mediated alleviation of this phenotype was Ssb-dependent. These results demonstrate a network of interactions that supports a hypothesis where Snl1 plays a role in translation regulation.

进行了这项研究，以更好地了解HSP70伴侣网络中的NEF角色。这些动态对于获得成功的治疗方法至关重要，这些治疗方法可以扭转神经退行性疾病（例如阿尔茨海默氏病和帕金森氏病）的衰弱作用。分子伴侣及其联合因素（例如NEFS）的药理学靶向是一个有吸引力的治疗目标，可能有助于改善人类健康，尤其是在老龄化的人群中。

Research Info

Functional analysis of cytosolic Hsp70 nucleotide exchange factor networks in yeast