Yeast DJ-1 superfamily members are required for diauxic-shift reprogramming and cell survival in stationary phase

Abstract

The yeast Hsp31 minifamily proteins (Hsp31, Hsp32, Hsp33, Hsp34) belong to the highly conserved DJ-1 superfamily. The human DJ-1 protein is associated with cancer and neurodegenerative disorders, such as Parkinson disease. However, the precise function of human and yeast DJ-1 proteins is unclear. Here we show that the yeast DJ-1 homologs have a role in diauxic-shift (DS), characterized by metabolic reprogramming because of glucose limitation. We find that the Hsp31 genes are strongly induced in DS and in stationary phase (SP), and that deletion of these genes reduces chronological lifespan, impairs transcriptional reprogramming at DS, and impairs the acquisition of several typical characteristics of SP, including autophagy induction. In addition, under carbon starvation, the HSP31 family gene-deletion strains display impaired autophagy, disrupted target of rapamycin complex 1 (TORC1) localization to P-bodies, and caused abnormal TORC1-mediated Atg13 phosphorylation. Repression of TORC1 by rapamycin in the gene-deletion strains completely reversed their sensitivity to heat shock. Taken together, our data indicate that Hsp31 minifamily is required for DS reprogramming and cell survival in SP, and plays a role upstream of TORC1. The enhanced understanding of the cellular function of these genes sheds light into the biological role of other members of the superfamily, including DJ-1, which is an attractive target for therapeutic intervention in cancer and in Parkinson disease.

Hsp31 Is a Stress Response Chaperone That Intervenes in the Protein Misfolding Process

“…4B). This increased expression in response to an ROS-inducing agent has been observed previously (22,26).…”

“…In yeast, deletion of the ATG1 gene reduced the clearance of ␣Syn aggregates (66). Deletion of HSP31 was also demonstrated to impair autophagy under carbon starvation conditions (22). These studies raise the possibility that Hsp31 could be promoting autophagy of aggregated protein.…”

“…A recent study demonstrated increased HSP31 mRNA levels upon treatment with H 2 O 2 , during the diauxic shift growth phase and stationary phase (22). However, the Hsp31 protein level was not characterized under these conditions.…”

“…The cellular functions of DJ-1 and E. coli hchA have been characterized, and their multifunctional roles in mediating oxidative stress, chaperone-like activity, methylglyoxalase activity, and cytoprotection have been described (10,15,16,19). There has been limited characterization of the cellular functions of Hsp31, but several recent studies have demonstrated that it has glyoxylase activity (20), chaperone activity (21), and a role in autophagy (22).…”

Metabolic role for yeast DJ-1 superfamily proteins

“…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.…”