A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast

• Published in: The Journal of biological chemistry Vol. 290; no. 34; pp. 21141 - 21153
• Main Authors: Mathiassen, Søs G., Larsen, Ida B., Poulsen, Esben G., Madsen, Christian T., Papaleo, Elena, Lindorff-Larsen, Kresten, Kragelund, Birthe B., Nielsen, Michael L., Kriegenburg, Franziska, Hartmann-Petersen, Rasmus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino Acid Sequence; chaperone; Coenzymes - chemistry; Coenzymes - metabolism; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Models, Molecular; Molecular Sequence Data; Mutation; Oncogene Proteins - chemistry; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Parkinson disease; Parkinson disease (autosomal recessive, early onset) 7 (PARK7); proteasome; Proteasome Endopeptidase Complex - metabolism; Protein Aggregates; Protein Deglycase DJ-1; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Synthesis and Degradation; Proteolysis; proteostasis; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; Sequence Alignment; Sequence Homology, Amino Acid; ubiquitin; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Parkinson disease; proteasome; chaperone; proteostasis; Parkinson disease (autosomal recessive, early onset) 7 (PARK7); ubiquitin
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M115.662312

A mutation, L166P, in the cytosolic protein, PARK7/DJ-1, causes protein misfolding and is linked to Parkinson disease. Here, we identify the fission yeast protein Sdj1 as the orthologue of DJ-1 and calculate by in silico saturation mutagenesis the effects of point mutants on its structural stability. We also map the degradation pathways for Sdj1-L169P, the fission yeast orthologue of the disease-causing DJ-1 L166P protein. Sdj1-L169P forms inclusions, which are enriched for the Hsp104 disaggregase. Hsp104 and Hsp70-type chaperones are required for efficient degradation of Sdj1-L169P. This also depends on the ribosome-associated E3 ligase Ltn1 and its co-factor Rqc1. Although Hsp104 is absolutely required for proteasomal degradation of Sdj1-L169P aggregates, the degradation of already aggregated Sdj1-L169P occurs independently of Ltn1 and Rqc1. Thus, our data point to soluble Sdj1-L169P being targeted early by Ltn1 and Rqc1. The fraction of Sdj1-L169P that escapes this first inspection then forms aggregates that are subsequently cleared via an Hsp104- and proteasome-dependent pathway. Background: A mutation, L166P, in DJ-1, is linked to Parkinson disease. Results: The Sdj1-L169P fission yeast orthologue of DJ1-L166P is misfolded, associated with chaperones, and degraded via two ubiquitin-proteasome dependent pathways. Conclusion: Sdj1-L169P is subject to a two-step degradation pathway. Significance: Mapping the degradation pathways for misfolded proteins is important for our basic understanding of protein quality control in health and disease.