DNAJB chaperones suppress destabilised protein aggregation via a region unique from that used to inhibit amyloidogenesis

Shannon McMahon, Steven Bergink, Harm H Kampinga, Heath Ecroyd*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    15 Citations (Scopus)
    206 Downloads (Pure)

    Abstract

    Disturbances to protein homeostasis (proteostasis) can lead to protein aggregation and inclusion formation, processes associated with a variety of neurodegenerative disorders. DNAJBs are molecular chaperones which have been identified as potent suppressors of disease-related protein aggregation. In this work, a destabilised isoform of firefly luciferase (R188Q/R261Q Fluc; FlucDM) was overexpressed in cells to assess the capacity of DNAJBs to inhibit inclusion formation. Co-expression of all DNAJBs tested significantly inhibited the intracellular aggregation of FlucDM Moreover, we show that DNAJBs suppress aggregation by supporting the Hsp70-dependent degradation of FlucDM via the proteasome. The serine-rich stretch in DNAJB6 and DNAJB8, essential for preventing fibrillar aggregation, is not involved in the suppression of FlucDM inclusion formation. Conversely, deletion of the C-terminal TTK-LKS motif in DNAJB6 and DNAJB8, a region not required to suppress polyQ aggregation, abolished its ability to inhibit inclusion formation by FlucDM Thus, our data suggest that DNAJB6 and DNAJB8 possess two distinct regions for binding substrates, one that is responsible for binding β-hairpins that form during amyloid formation and another that interacts with exposed hydrophobic patches in aggregation-prone clients.

    Original languageEnglish
    Article number255596
    Number of pages13
    JournalJournal of Cell Science
    Volume134
    Issue number7
    Early online date2021
    DOIs
    Publication statusPublished - Apr-2021

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