Nuclear import carrier Hikeshi cooperates with HSP70 to promote murine oligodendrocyte differentiation and CNS myelination.

Dysregulation of factors in nucleocytoplasmic transport is closely linked to neural developmental diseases. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of heat shock protein 70 family (HSP70s), leads to inherited leukodystrophy; however, the pathological mechanisms remain elusive. Here, we showed that Hikeshi is essential for central nervous system (CNS) myelination. Deficiency of Hikeshi, which is observed in inherited leukodystrophy patients, resulted in murine oligodendrocyte maturation arrest. Hikeshi is required for nuclear translocation of HSP70s upon differentiation. Nuclear-localized HSP70 promotes murine oligodendrocyte differentiation and remyelination after white matter injury. Mechanistically, HSP70s interacted with SOX10 in the nucleus and protected it from E3 ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, these findings demonstrate that Hikeshi-mediated nuclear translocation of HSP70s is essential for myelinogenesis and provide insights into pathological mechanisms of Hikeshi-related leukodystrophy.

Electrochemical ammonia synthesis by reduction of nitrate on Au doped Cu nanowires.

Electrochemical nitrate reduction reaction (NO3 -RR) to synthesize valuable ammonia (NH3) is considered as a green and appealing alternative to enable an artificial nitrogen cycle. However, as there are other NO3 -RR pathways present, selectively guiding the reaction pathway towards NH3 is currently challenged by the lack of efficient catalyst. Here, we demonstrate a novel electrocatalyst for NO3 -RR consisting of Au doped Cu nanowires on a copper foam (CF) electrode (Au-Cu NWs/CF), which delivers a remarkable NH3 yield rate of 5336.0 ± 159.2 µg h-1 cm-2 and an exceptional faradaic efficiency (FE) of 84.1 ± 1.0% at -1.05 V (vs. RHE). The 15N isotopic labelling experiments confirm that the yielded NH3 is indeed from the Au-Cu NWs/CF catalyzed NO3 -RR process. The XPS analysis and in situ infrared spectroscopy (IR) spectroscopy characterization results indicated that the electron transfer between the Cu and Au interface and oxygen vacancy synergistically decreased the reduction reaction barrier and inhibited the generation of hydrogen in the competitive reaction, resulting in a high conversion, selectivity and FE for NO3 -RR. This work not only develops a powerful strategy for the rational design of robust and efficient catalysts by defect engineering, but also provides new insights for selective nitrate electroreduction to NH3.

Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling.

Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.