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Human DnaJB6 anti-amyloid chaperone protects yeast from polyglutamine toxicity separately from spatial segregation of aggregates

Thursday, September 13, 2018 — Poster Session IV

3:30 p.m. – 5:00 p.m.
FAES Terrace
NIDDK
CELLBIO-7

Authors

  • J Kumar
  • NL Kline
  • DC Masison

Abstract

Accumulation of polyglutamine (polyQ) aggregates is associated with pathology in several protein-folding diseases and with toxicity in the yeast Saccharomyces cerevisiae. Protection from polyQ toxicity in yeast by J-protein co-chaperone DnaJB6 coincides with sequestration of smaller aggregates into single large structures. Various cellular protein quality control (PQC) factors can gather misfolded proteins into large deposition sites, which has led to a common view that PQC processes can neutralize toxic aggregates by collecting them into benign, spatially segregated compartments. Whether DnaJB6 depends on this machinery to sequester polyQ aggregates, if this sequestration is needed for DnaJB6 to protect cells, and the identity of the focal structure are unknown. Here we found that DnaJB6-driven focal deposits share characteristics with peri-vacuolar insoluble protein deposition sites (IPODs). Binding of DnaJB6 to polyQ aggregates was necessary, but not enough for detoxification. We also found that focal formation required a DnaJB6-heat shock protein 70 (Hsp70) interaction and actin, that polyQ could be detoxified without focal formation, and that spatial segregation of polyQ aggregates alone did not provide protection. Our findings, which align with earlier work showing DnaJB6 binds polyQ oligomers and amyloid, suggest DnaJB6 binds to smaller polyQ aggregates to block their toxicity. Subsequent assembly and spatial segregation of detoxified aggregates is driven by an actin-dependent process requiring DnaJB6-Hsp70 cooperation. Our findings reveal that sequestration of polyQ aggregates is not the primary mechanism by which DnaJB6 suppresses toxicity and raise questions regarding how and when misfolded proteins are detoxified during spatial segregation processes.

Category: Cell Biology