HspB8 Participates in Protein Quality Control by a Non-chaperone-like Mechanism That Requires eIF2 alpha Phosphorylation

Serena Carra*, Jeanette F. Brunsting, Herman Lambert, Jacques Landry, Harm H. Kampinga

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    101 Citaten (Scopus)

    Samenvatting

    Aggregation of mutated proteins is a hallmark of many neurodegenerative disorders, including Huntington disease. We previously reported that overexpression of the HspB8 . Bag3 chaperone complex suppresses mutated huntingtin aggregation via autophagy. Classically, HspB proteins are thought to act as ATP-independent molecular chaperones that can bind unfolded proteins and facilitate their processing via the help of ATP-dependent chaperones such as the Hsp70 machine, in which Bag3 may act as a molecular link between HspB, Hsp70, and the ubiquitin ligases. However, here we show that HspB8 and Bag3 act in a non-canonical manner unrelated to the classical chaperone model. Rather, HspB8 and Bag3 induce the phosphorylation of the alpha-subunit of the translation initiator factor eIF2, which in turn causes a translational shut-down and stimulates autophagy. This function of HspB8 . Bag3 does not require Hsp70 and also targets fully folded substrates. HspB8 . Bag3 activity was independent of the endoplasmic reticulum (ER) stress kinase PERK, demonstrating that its action is unrelated to ER stress and suggesting that it activates stress-mediated translational arrest and autophagy through a novel pathway.

    Originele taal-2English
    Pagina's (van-tot)5523-5532
    Aantal pagina's10
    TijdschriftThe Journal of Biological Chemistry
    Volume284
    Nummer van het tijdschrift9
    DOI's
    StatusPublished - 27-feb-2009

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