The laforin/malin E3-ubiquitin ligase complex ubiquitinates members of the Hsp70 and Hsp90 protein families

The presence of misfolded and aggregated proteins presents a problem in cellular protein homeostasis. To avoid this, cells have evolved powerful protein quality control systems that ensure proper folding or disposal of misfolded and aggregated proteins. Some of these systems are the ATP-dependent chaperones, such as Hsp70s and Hsp90s. Through cycles of binding to substrates and ATP hydrolysis, and with the help of additional co-chaperones, these systems participate in the proper folding of misfolded proteins. The activity of the Hsp70s and Hsp90s is regulated by post-translational modifications, one of them being ubiquitination. In this work, we present evidence of the participation of the laforin/malin complex in the ubiquitination of several components of the Hsp70s and Hsp90s systems, such as HspA1L, Hsp90α, Hsp90β and the co-chaperone Hop/Stip1. In addition, we show that there is a physical interaction between HspA1L and both laforin and malin. In the case of Hsp90α, we observed an interaction with malin but not with laforin, and in the case of Hop/Stip1, both laforin and malin are needed for the interaction with this co-chaperone. Our work identifies the laforin/malin complex as a new E3-ubiquitin ligase that introduces post-translational modifications in these proteins, which may regulate their activity.