Dysregulation of the ubiquitin–proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2–VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination. Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI. Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for Nedd4 in glial biology.
Wnt signaling plays a critical role in development across species and is dysregulated in a host of human diseases. A key step in signal transduction is the formation of Wnt receptor signalosomes, during which a large number of components translocate to the membrane, cluster together and amplify downstream signaling. However, the molecular processes that coordinate these events remain poorly defined. Here, we show that Daam2 regulates canonical Wnt signaling via the PIP2–PIP5K axis through its association with Rac1. Clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K, and PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner. Importantly, the localization of Daam2 complexes and Daam2-mediated canonical Wnt signaling is dependent upon actin polymerization. These studies – in chick spinal cord and human and monkey cell lines – highlight novel roles for Rac1 and the actin cytoskeleton in the regulation of canonical Wnt signaling and define Daam2 as a key scaffolding hub that coordinates membrane translocation and signalosome clustering.
Acute graft-versus-host disease (GvHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises anti-tumor and anti-pathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T-cells in acute GvHD and plays a central role in driving the expansion of alloreactive T-cells. Here, we show that OX40 is also upregulated on T-cells infiltrating GvHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T-cells will mitigate GvHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T-cells, enables selective elimination of OX40+ T-cells. Because OX40 is primarily upregulated on CD4+ T-cells upon activation, engineered OX40-specific T-cells mediated potent cytotoxicity against activated CD4+ T-cells and suppressed alloreactive T-cell expansion in a mixed lymphocyte reaction model. OX40 targeting did not inhibit anti-viral activity of memory T-cells specific to EBV, CMV, and adenoviral antigens. Systemic administration of OX40-targeting T-cells fully protected mice from fatal xenogeneic GvHD mediated by human PBMCs. Further, combining OX40 targeting with a leukemia-specific chimeric antigen receptor (CAR) in a single T-cell product provides simultaneous protection against leukemia and acute GvHD in a mouse xenograft model of residual disease post-transplant. These results underscore the central role of OX40+ T-cells in mediating acute GvHD pathogenesis and support the feasibility of a bi-functional engineered T-cell product derived from the stem cell donor to suppress both disease relapse and acute GvHD following allo-HSCT.
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