No abstract

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID‐19) pandemic is used to discover three highly potent antibodies that selectively bind SARS‐CoV‐2 spike protein and neutralize authentic SARS‐CoV‐2 virus. Compared to neutralizing antibodies from COVID‐19 patients with generally low somatic hypermutation (SHM), these three antibodies contain over 13–22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS‐CoV‐2 spike receptor binding domain. The identification of these somatically mutated antibodies in a pre‐pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS‐CoV‐2.

Peroxisome proliferator-activated receptor (PPAR)-γ is a key transcription activator controlling adipogenesis and lipid metabolism. PPARγ binds PPAR response elements (PPREs) as the obligate heterodimer with retinoid X receptor (RXR) α, but exactly how PPARγ orchestrates the transcriptional response is unknown. This study demonstrates that PPARγ forms phase-separated droplets in vitro and solid-like nuclear condensates in cell, which is intriguingly mediated by its DNA binding domain characterized by the zinc finger motif. Furthermore, PPARγ forms nuclear condensates at PPREs sites through phase separation to compartmentalize its heterodimer partner RXRα to initiate PPARγ-specific transcriptional activation. Finally, using an optogenetic approach, the enforced formation of PPARγ/RXRα condensates leads to preferential enrichment at PPREs sites and significantly promotes the expression of PPARγ target genes. These results define a novel mechanism by which PPARγ engages the phase separation principles for efficient and specific transcriptional activation.

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The emergence of SARS-CoV-2 variants poses enormous challenges to the prevention and control of COVID-19 with alterations in antigenicity, transmissibility and pathogenicity. The rapid evolution of RNA viruses could be caused by high mutation frequencies during replication, arising by replication errors, intergenomic recombination or even host deaminases. We sought to understand whether host deaminases are involved in SARS-CoV-2 mutation, and how they orchestrate host deaminases to trigger this process. Herein, we provided the experimental evidence that APOBEC and ADAR deaminases act as the driving forces for SARS-CoV-2 mutagenesis. Mechanistically, SARS-CoV-2 nucleocapsid (N) protein, which is responsible for packaging viral genomic RNA, complexes with host deaminases to facilitate viral RNA mutation. Moreover, N protein employs deaminases-involved condensates to further promote viral RNA mutation. Mutant N protein with F17A substitution, defective in entry of deaminases-involved RNA granules, leads to the decreased mutation of viral RNA, confirming the function of N protein-deaminase condensates on RNA editing. Our study sheds light on the novel mechanism of SARS-CoV-2 mutation during host-virus arms race.