The Ubiquitin Ligase Zinc Finger SWIM Domain-Containing Protein 8 Regulates Oligodendrocyte Development Through the Argonaute2/MicroRNA-7 Axis.

Proteostasis of proteins with intrinsically disordered regions (IDRs) is of particular importance to the development and function of the central nervous system (CNS). The conserved ZSWIM8 ubiquitin ligase, an essential regulator of mammalian brain development, is known to target IDR proteins involved in neuronal cell migration. Here we show that ZSWIM8 is also indispensable for oligodendrocyte maturation and myelination in the CNS. Loss of ZSWIM8 in the brain causes gross accumulation of IDR-rich proteins including many RNA-binding proteins (RBPs). Substrate recognition by ZSWIM8 requires its own IDRs, while ZSWIM8-mediated ubiquitination of AGO2 also depends on microRNA binding. AGO2 stabilization in ZSWIM8-null tissues disrupts target-directed microRNA degradation (TDMD) of MiR7, leading to altered gene expressions and myelination defects in vivo. Together, these results not only establish ZSWIM8 as a versatile regulator of IDR proteins but also highlight the crucial roles of RBP/miRNA homeostasis in oligodendrocyte development.