Preprint: Conserved mycobacteriophage protein uses structural mimicry to displace host initiation factors

Phages carry compact genomes, yet they reprogram host gene expression within minutes of infection. In this preprint, co-led by David Parker and Shrestha Ghosh in the lab together with Adela Dujiskova (Rockefeller University), we looked at how mycobacteriophages achieve this takeover.

Using time-resolved interaction proteomics across infection with mycobacteriophage D29, we identified a two-protein module, gp53–gp52, that associates with the host RNA polymerase. Affinity purification confirmed the interaction, and native mass spectrometry showed that gp53 displaces the host sigma factor from the polymerase. Structural modelling places gp53 on the sigma-binding surface, indicating that the phage protein works through structural mimicry rather than by degrading or sequestering host factors.

The module is conserved across Cluster A mycobacteriophages, appearing in both fused and split genomic arrangements, suggesting it is a general strategy for transcriptional hijacking in this group rather than a one-off solution.

This study was a collaborative effort with Elizabeth Campbell and Paul Dominic B. Olinares (Rockefeller University), Arne Elofsson and Sarah Narrowe Danielsson (Stockholm University/SciLifeLab), and Matthias Mann and Florian A. Rosenberger (Max Planck Institute of Biochemistry).

Read the preprint: Conserved mycobacteriophage protein uses structural mimicry to displace host initiation factors →