Rewriting the viral script: post-translational modifications orchestrating SARS-CoV-2 pathogenesis and immune evasion

SARS-CoV-2 reprograms host cell biology not solely through its genomic content but also through a sophisticated arsenal of post-translational modifications (PTMs) that modulate viral protein function, host signaling networks, and immune responses. Despite increasing recognition of PTMs as dynamic regulators of infection, their full functional breadth and therapeutic potential remain incompletely defined. Here, we provide a comprehensive, PTM-centric synthesis of SARS-CoV-2 pathogenesis, detailing how phosphorylation, ubiquitination, SUMOylation, glycosylation, acetylation, succinylation, ISGylation, and ADP-ribosylation cooperatively shape virus-host interplay. We dissect the mechanistic roles of individual modifications, such as phosphorylation-mediated transitions in nucleocapsid function, ubiquitin-driven degradation of immune factors, and SUMOylation-guided viral assembly, while revealing higher-order regulatory circuits and crosstalk among PTMs. Additionally, we highlight emerging computational tools for PTM site prediction and identify shared enzymatic nodes exploitable for host-directed antiviral strategies. This integrative framework positions PTMs as not merely bystanders but as central modulators of viral fitness and host vulnerability, offering novel avenues for therapeutic intervention against SARS-CoV-2 and future pandemic threats.