J Proteins Counteract Amyloid Propagation and Toxicity in Yeast.

Abstract

Simple SummaryDozens of diseases are associated with misfolded proteins that accumulate in highly ordered fibrous aggregates called amyloids. Protein quality control (PQC) factors keep cells healthy by helping maintain the integrity of the cell’s proteins and physiological processes. Yeast has been used widely for years to study how amyloids cause toxicity to cells and how PQC factors help protect cells from amyloid toxicity. The so-called J-domain proteins (JDPs) are PQC factors that are particularly effective at providing such protection. We discuss how PQC factors protect animals, human cells, and yeast from amyloid toxicity, focusing on yeast and human JDPs.The accumulation of misfolded proteins as amyloids is associated with pathology in dozens of debilitating human disorders, including diabetes, Alzheimer’s, Parkinson’s, and Huntington’s diseases. Expressing human amyloid-forming proteins in yeast is toxic, and yeast prions that propagate as infectious amyloid forms of cellular proteins are also harmful. The yeast system, which has been useful for studying amyloids and their toxic effects, has provided much insight into how amyloids affect cells and how cells respond to them. Given that an amyloid is a protein folding problem, it is unsurprising that the factors found to counteract the propagation or toxicity of amyloids in yeast involve protein quality control. Here, we discuss such factors with an emphasis on J-domain proteins (JDPs), which are the most highly abundant and diverse regulators of Hsp70 chaperones. The anti-amyloid effects of JDPs can be direct or require interaction with Hsp70.