RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination.

Maldevelopment of oligodendroglia underlies neural developmental disorders such as leukodystrophy. Precise regulation of the activity of specific transcription factors (TFs) by various posttranslational modifications (PTMs) is required to ensure proper oligodendroglial development and myelination. However, the role of ubiquitination of these TFs during oligodendroglial development is yet unexplored. Here, we find that RNF220, a known leukodystrophy-related E3 ubiquitin ligase, is required for oligodendroglial development. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, which consequently leads to learning and memory defects. Mechanistically, RNF220 targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development. Furthermore, in a knock-in mouse model of leukodystrophy-related RNF220R365Q mutation, the ubiquitination and stabilization of Olig proteins are deregulated in oligodendroglial cells. This results in pathomimetic oligodendroglial developmental defects, impaired myelination, and abnormal behaviors. Together, our evidence provides an alternative insight into PTMs of oligodendroglial TFs and how this essential process may be implicated in the etiology of leukodystrophy.

Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. METHODS: We analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection. FINDINGS: The BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo. INTERPRETATION: These results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19. FUNDING: This study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS "Light of West China" Program, and Yunnan Province (202305AH340006).