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bioRxiv · 10.64898/2026.01.27.700999

Phage Portal Proteins Suppress Bacterial Stringent Response to Promote Infection

Kronborg, K.·Wang, L.·Schicketanz, M.·Gerdes, K.·ZHANG, Y.
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Abstract

Bacteria restrict viral replication not only through dedicated defense systems but also by entering global physiological states that limit cellular resources. How phages counter such host-imposed physiological barriers remains poorly understood. The stringent response (SR), mediated by the alarmones ppGpp and pppGpp, induces a growth-restrictive state that can act as a barrier to bacteriophage infection. Here we show that elevated alarmone levels delay T7-mediated host lysis, whereas (p)ppGpp-deficient cells are hypersensitive to infection, establishing alarmone signaling as a physiological constraint on phage replication. A systematic functional screen identifies the essential capsid portal protein Gp8 as a viral factor genetically linked to SR-dependent host physiology. Gp8 directly binds the alarmone synthetases RelA and SpoT, selectively inhibiting their synthetase activities in vitro and suppressing alarmone accumulation in vivo. Phages carrying interaction-defective portal mutations exhibit impaired replication, delayed lysis, and sustained (p)ppGpp elevation during infection, defects that are alleviated in SR-deficient hosts. Structural and mutational analyses reveal electrostatically mediated interfaces required for targeting RelA and SpoT. Portal proteins from diverse coliphages share similar structural features, interact with stringent-response enzymes, and display SR-linked phenotypes, indicating a broadly conserved viral strategy. Together, these findings identify phage portal proteins as a previously unrecognized class of viral counter-defense factors that target a central bacterial stress signaling pathway, revealing that essential structural virion components can moonlight as regulators of host stress physiology.

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Kronborg, K., Wang, L., Schicketanz, M., Gerdes, K., ZHANG, Y.. 2026-01-27. Phage Portal Proteins Suppress Bacterial Stringent Response to Promote Infection. https://doi.org/10.64898/2026.01.27.700999

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