TY - JOUR
T1 - Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks
AU - Meister-Broekema, Melanie
AU - Freilich, Rebecca
AU - Jagadeesan, Chandhuru
AU - Rauch, Jennifer N.
AU - Bengoechea, Rocio
AU - Motley, William W.
AU - Kuiper, E. F.Elsiena
AU - Minoia, Melania
AU - Furtado, Gabriel V.
AU - van Waarde, Maria A.W.H.
AU - Bird, Shawn J.
AU - Rebelo, Adriana
AU - Zuchner, Stephan
AU - Pytel, Peter
AU - Scherer, Steven S.
AU - Morelli, Federica F.
AU - Carra, Serena
AU - Weihl, Conrad C.
AU - Bergink, Steven
AU - Gestwicki, Jason E.
AU - Kampinga, Harm H.
N1 - Funding Information:
We are grateful to Telethon Genetic BioBank (GTB12001D to E.P.) and Eurobiobank Network for providing the patient fibroblasts. H.H.K. was involved in a regional initiative (SNN project Transitie II & Pieken) called ChaperoneAge, a consortium with commercial partners Syncom, ABL, Axon MedChem, Nyken, Brains-on-line, Angita Pharma and the RuG/UMCG. H.H.K. and S.C. received research grants from Prinses Beatrix Spierfonds; H.H.K. received grants from the Hersenstichting, the High-Q foundation, the Ministry of Economic Affaires (senternoven.nl), the National Ataxia Foundation, and the Dutch Heart Society (Hartedroom project 2013T088 and CVON-2014-40). S.C. was supported for initiating this work by an AFM trampoline grant (14492-MNM1 2012-Funding Myologie) and by a Telethon grant (GGP 15001). S.B. received grants from the Hersenstichting and NWO-ALW. M.M.B. was a graduate student at the University Medical Center Groningen at the time the study was conducted and is currently employed by PAREXEL International. J.E.G. received grants from the US National Institutes of Health (NS059690) and the Tau Consortium. C.C.W. is supported by NIH R01 AR068797 and a research grant from the MDA.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.
AB - BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.
UR - http://www.scopus.com/inward/record.url?scp=85058731556&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07718-5
DO - 10.1038/s41467-018-07718-5
M3 - Article
C2 - 30559338
AN - SCOPUS:85058731556
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5342
ER -