HERC4 limits oxidative stress-induced DNA damage during bacterial and viral-bacterial infection

Cammann, C.; Gering, V.; Sura, T.; Singh, A. K.; Boehme, J. D.; Topfstedt, E.; Koch, A. K.; Ritter, U.; Becker, K.; Bruder, D.; Blohm, U.; Slevogt, H.; Maass, S.; Rohde, G.; Rupp, J.; CAPNetz Study Group,; Hammerschmidt, S.; Becher, D.; Seifert, U.

doi:10.64898/2026.07.02.736007

bioRxiv · 10.64898/2026.07.02.736007

HERC4 limits oxidative stress-induced DNA damage during bacterial and viral-bacterial infection

Cammann, C.·Gering, V.·Sura, T.·Singh, A. K.·Boehme, J. D.·Topfstedt, E.·Koch, A. K.·Ritter, U.·Becker, K.·Bruder, D.·Blohm, U.·Slevogt, H.·Maass, S.·Rohde, G.·Rupp, J.·CAPNetz Study Group,·Hammerschmidt, S.·Becher, D.·Seifert, U.

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Abstract

Respiratory (co-)infections caused by influenza viruses and Streptococcus pneumoniae represent significant threats to global health. In our analysis of host cell ubiquitination, we identified reactive oxygen species (ROS) produced by S. pneumoniae as critical effectors in reducing the amount of intracellular polyubiquitinated proteins. Together with reduced ubiquitination we observed a downregulation of the E3 ligase HERC4 upon infection with S. pneumoniae in human alveolar epithelial and macrophage-like cells as well as in samples obtained from S. pneumoniae infected humans and mice. This was further aggravated in the viral-bacterial coinfection with influenza A. CRISPR-Cas9 deletion of HERC4 prior bacterial infection resulted in increased ROS-induced DNA damage, enhanced host cell apoptosis and reduced Histone 2B ubiquitination. In contrast, HERC4 overexpression diminished DNA damage indicating a role of HERC4 in DNA-damage-repair upon infection. By establishing a link between HERC4 expression and ROS-induced DNA damage and repair, we identified a potential marker for predicting the outcome of viral and bacterial (co-)infections. Targeting HERC4 expression defines a novel strategy to protect host cells from S. pneumoniae (co-)infection attenuating infection exacerbation.

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Cammann, C., Gering, V., Sura, T., Singh, A. K., Boehme, J. D., Topfstedt, E., Koch, A. K., Ritter, U., Becker, K., Bruder, D., Blohm, U., Slevogt, H., Maass, S., Rohde, G., Rupp, J., CAPNetz Study Group,, Hammerschmidt, S., Becher, D., Seifert, U.. 2026-07-04. HERC4 limits oxidative stress-induced DNA damage during bacterial and viral-bacterial infection. https://doi.org/10.64898/2026.07.02.736007

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