The comprehensive SARS-CoV-2 ‘hijackome’ knowledge base— reveals significant changes in host cell protein expression and activation by multiple SARS-CoV-2 variants

Abstract The continuous evolution of SARS-CoV-2 has led to the emergence of several variants of concern (VOCs) that significantly affect global health. This study aims to investigate how these VOCs affect host cells at proteome level to better understand the mechanisms of disease. To achieve this, we first analyzed the (phospho)proteome changes of host cells infected with Alpha, Beta, Delta, and Omicron BA.1 and BA.5 variants over time frames extending from 1 to 36 hours post-infection. Our results revealed distinct temporal patterns of protein expression across the VOCs, with notable differences in the (phospho)proteome dynamics that suggest variant-specific adaptations. Specifically, we observed enhanced expression and activation of key components within crucial cellular pathways such as the RHO GTPase cycle, RNA splicing, and ER-associated degradation (ERAD)-related processes. We further utilized proximity biotinylation Mass Spectrometry (BioID-MS) to investigate how specific mutation of these VOC influence viral-host protein interactions. Our comprehensive interactomics dataset uncovers distinct interaction profiles for each variant, illustrating on how specific mutations can change viral protein functionality. Overall, our extensive analysis provides a detailed proteomic profile of host cell for each variant, offering valuable insights into how specific mutations may influence viral protein functionality and impact therapeutic target identification. These insights are crucial for the design of new targeted interventions, aiming to enhance the efficacy of treatments against evolving SARS-CoV-2 variants.