Hikeshi-Mediated Nuclear Translocation of HSP70 Promotes Myelinogenesis by Preventing FBXW7-mediated Degradation of Sox10

Dysregulation of nucleocytoplasmic transport is intensively linked to many neurological diseases. Heat shock proteins 70 (HSP70s), which dramatically change its cellular localization upon stress, play important regulatory roles in nervous system. How the localization of HSP70s is regulated and the underlying physiological functions of this translocation are both poorly understood. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of HSP70s, lead to inherited leukodystrophy; however, the underlying mechanisms remain poorly understood. Here we showed that Hikeshi and HSP70s are essential for proper CNS myelination and remyelination. Loss of Hikeshi resulted in oligodendrocyte maturation arrest through preventing the nuclear translocation of HSP70s upon oligodendrocyte differentiation. HSP70s interacted with Sox10SOX10 in the nucleus and protected it from E3 ubiquitin ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that the Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, we demonstrate that Hikeshi-dependent nuclear translocation of HSP70s is essential for oligodendrocyte differentiation and myelinogenesis, and suggest the potential therapeutic value of hyperthermia therapy in myelin repair. Overall design: RNA-seq was performed on rat siSCR or siHsc70 immature oligodendrocytes (T3 D2).