Photochemical Identification of Auxiliary Severe Acute Respiratory Syndrome Coronavirus 2 Host Entry Factors Using μMap. Author Saori Suzuki, Jacob Geri, Steve Knutson, Harris Bell-Temin, Tomokazu Tamura, David Fernández, Gabrielle Lovett, Nicholas Till, Brigitte Heller, Jinchao Guo, David MacMillan, Alexander Ploss Publication Year 2022 Type Journal Article Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of the COVID-19 pandemic, remains a global medical problem. Angiotensin-converting enzyme 2 () was identified as the primary viral entry receptor, and transmembrane serine protease 2 primes the spike protein for membrane fusion. However, expression is generally low and variable across tissues, suggesting that auxiliary receptors facilitate viral entry. Identifying these factors is critical for understanding SARS-Cov-2 pathophysiology and developing new countermeasures. However, profiling host-virus interactomes involves extensive genetic screening or complex computational predictions. Here, we leverage the photocatalytic proximity labeling platform μMap to rapidly profile the spike interactome in human cells and identify eight novel candidate receptors. We systemically validate their functionality in SARS-CoV-2 pseudoviral uptake assays with both Wuhan and Delta spike variants and show that dual expression of with either neuropilin-2, ephrin receptor A7, solute carrier family 6 member 15, or myelin and lymphocyte protein 2 significantly enhances viral uptake. Collectively, our data show that SARS-CoV-2 synergistically engages several host factors for cell entry and establishes μMap as a powerful tool for rapidly interrogating host-virus interactomes. Keywords Humans, Protein Binding, Virus Internalization, Pandemics, COVID-19, SARS-CoV-2, Angiotensin-Converting Enzyme 2, Spike Glycoprotein, Coronavirus, Peptidyl-Dipeptidase A Journal J Am Chem Soc Volume 144 Issue 36 Pages 16604-16611 Date Published 2022 Sep 14 ISSN Number 1520-5126 DOI 10.1021/jacs.2c06806 Alternate Journal J Am Chem Soc PMCID PMC9469761 PMID 36049228 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML