Biology subjects

Solow-Cordero, D. E.

Publications and source records attributed to Solow-Cordero, D. E..

3 recordsLinked to original sources

bioRxiv2026

Ratiometric transcriptional activation by protein degradation

Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcriptional inhibitor-protein of interest fusion and transcription factor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.

synthetic biology↗

bioRxiv2021

Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2

Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). To identify additional ways of reducing ataxin-2 levels, we performed a genome-wide screen in human cells for regulators of ataxin-2 and identified RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a top hit. RTN4R knockdown, or treatment with a peptide inhibitor, was sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. Remarkably, we observed that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.

neuroscience↗

bioRxiv2021

Pan-ErbB inhibition protects from SARS-CoV-2 replication, inflammation, and injury

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

microbiology↗