Biology subjects

Gui, X.

Publications and source records attributed to Gui, X..

3 recordsLinked to original sources

bioRxiv2020

An antibody-dependent enhancement (ADE) activity eliminated neutralizing antibody with potent prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, showing high SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with Fc{gamma}RIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity was eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Most importantly, potent prophylactic and therapeutic effects against SARS-CoV-2 were observed in rhesus monkeys. A single dose of MW05/LALA completely blocked the infection of SARS-CoV-2 in a study of its prophylactic effect and totally cleared SARS-CoV-2 in three days in a treatment setting. These results pave the way for the development of MW05/LALA as an effective strategy for combating COVID-19.

microbiology↗

bioRxiv2020

The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-{beta}2 (Kap{beta}2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kap{beta}2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminate structural understandings on the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kap{beta}2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

biophysics↗

bioRxiv2020

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIF)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIF in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIF stabilization in oligodendroglia does not perturb Wnt signaling but remarkably activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIF-regulated CNS angiogenesis. Interestingly, blocking astroglia-derived Wnt signaling reduces astroglial HIF-regulated CNS angiogenesis. Together, our in vivo data clearly demonstrate that oligodendroglial HIF regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. Our findings represent an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIF-Wnt axis in regulating CNS vessel formation.

neuroscience↗