A proteome-scale map of the SARS-CoV-2–human contactome

Dae-Kyum Kim , Benjamin Weller , Chung-Wen Lin , Dayag Sheykhkarimli , Jennifer Knapp , Guillaume Dugied , Andreas Zanzoni (1) , Carles Pons , Marie Tofaute , Sibusiso Maseko , Kerstin Spirohn , Florent Laval , Luke Lambourne , Nishka Kishore , Ashyad Rayhan , Mayra Sauer , Veronika Young , Hridi Halder , Nora Marín-De La Rosa , Oxana Pogoutse , Alexandra Strobel , Patrick Schwehn , Roujia Li , Simin Rothballer , Melina Altmann , Patricia Cassonnet , Atina Coté , Lena Elorduy Vergara , Isaiah Hazelwood , Betty Liu , Maria Nguyen , Ramakrishnan Pandiarajan , Bushra Dohai , Patricia Coloma , Juline Poirson , Paolo Giuliana , Luc Willems , Mikko Taipale , Yves Jacob , Tong Hao , David Hill , Christine Brun (1) , Jean-Claude Twizere , Daniel Krappmann , Matthias Heinig , Claudia Falter , Patrick Aloy , Caroline Demeret , Marc Vidal , Michael Calderwood , Frederick Roth , Pascal Falter-Braun

1 TAGC - Theories and Approaches of Genomic Complexity

AbstractUnderstanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus–host contacts (the ‘contactome’) have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus–host and intraviral protein–protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular Networks [q-bio.MN]

Dae-Kyum Kim, Benjamin Weller, Chung-Wen Lin, Dayag Sheykhkarimli, Jennifer Knapp, et al.. A proteome-scale map of the SARS-CoV-2–human contactome. Nature Biotechnology, 2022, ⟨10.1038/s41587-022-01475-z⟩. ⟨hal-03832174⟩