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.

x as in both instances a loss of NPC function has been observed [8][9][10][11] . In particular, dividing cells depend on a constant supply of new NPCs, and indeed NPC assembly is compromised in mitotically aged yeast cells 10 .The mechanisms how FG-Nups are protected from making inappropriate interactions during NPC biogenesis are only beginning to liquid-liquid phase separate 5,6 and aggregate 7 , make NPC biogenesis a multi-step and complex event. Appearance of misassembled NPC intermediates or damaged NPCs is a risk to the cell as it could possibly lead to loss of compartmentalization. In ageing, as well as in disease, it becomes clear how NPC function is intricately interwoven with cell physiology, b WT DNAJB6 Lamin B1 Merge