Metabolic role for yeast DJ-1 superfamily proteins.

The DJ-1 superfamily comprises a mysterious assortment of proteins whose functions have been surprisingly difficult to elucidate. These diverse proteins are present in most organisms and are often associated with stress response; however, the biochemical mechanisms of only a few have been clearly established. Interest in this superfamily has been driven primarily by the involvement of human DJ-1 in rare forms of heritable parkinsonism (1). In addition, human DJ-1 is a weak oncogene (2) and has also been implicated in ischemia-reperfusion injury (3), making it an appealing target for understanding multiple diseases at the molecular level. Consequently, several model systems have been used to study the function of DJ-1 and its homologs, with an emerging consensus that animal DJ-1 is protective against oxidative stress and mitochondrial dysfunction by modulating the activities of multiple cytoprotective pathways (4). However, the details of DJ-1’s mechanism are actively debated, even after years of study. Saccharomyces cerevisiae has four homologs of DJ-1 (Hsp31, Hsp32, Hsp33, and Hsp34), the latter three of which are ∼99% identical to each other at the amino acid level. Therefore, this venerable model system presents some peculiar technical challenges to the study of DJ-1 superfamily proteins. The comprehensive study by MillerFleming et al., reported in PNAS, addresses these complications and finds that the S. cerevisiae Hsp31 minifamily plays a key role in the transition of proliferating yeast cells through diauxic shift then into a nonproliferative state known as stationary phase (5). The authors report that yeast Hsp31 family proteins are candidate upstream modulators of target of rapamycin complex 1 (TORC1), an important kinase that regulates nutrient sensing and cell proliferation and has been implicated in the function of human DJ-1 as well. Miller-Fleming et al. provide both a wealth of new data and a set of testable hypotheses that promise to drive the study of yeast Hsp31 proteins in the future. The Prior Understanding of Hsp31-Like Proteins Despite sharing a conserved core fold and some key residues, DJ-1 superfamily proteins differ widely in structure, oligomerization, and function. Consequently, the DJ-1 superfamily can be divided into multiple clades with distinct presumed functions (6, 7). Some of these proteins are degradative cysteine proteases, whereas others are