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ISG15-modification of the Arp2/3 complex restricts pathogen spread

de Yifeng Zhang, Brittany Ripley, Wei Ouyang, Miranda Sturtz, Ellen Upton, Emma Luhmann, Madeleine Vessely, Rocio Coloma, Nathan Schwery, Scott M. Anthony, Adam Goeken, Thomas O. Moninger, John T. Harty, Aloysius Klingelhutz, Emma Lundberg, David K. Meyerholz, Balaji Manicassamy, Christopher Stipp, Susana Guerra e Lilliana Radoshevich

Publicado: 27 de dezembro de 2022
Servidor: bioRxiv
DOI: 10.1101/2022.12.27.522022

Resumo

Summary

The ubiquitin-like protein, ISG15, can act as a cytokine or can covalently modify host and pathogen-derived proteins. The consequences of ISG15 modification on substrate fate remain unknown. Here we reveal that ISGylation of the Arp2/3 complex slows actin filament formation and stabilizes Arp2/3 dependent structures including cortical actin and lamella. When properly controlled, this serves as an antibacterial and antiviral host defense strategy to directly restrict actin-mediated pathogen spread. However, Listeria monocytogenes takes advantage in models of dysregulated ISGylation, leading to increased mortality due to augmented spread. The underlying molecular mechanism responsible for the ISG15-dependent impact on actin-based motility is due to failed bacterial separation after division. This promotes spread by enabling the formation of multi-headed bacterial “bazookas” with stabilized comet tails that can disseminate deeper into tissues. A bacterial mutant that cannot recruit Arp2/3 or a non-ISGylatable mutant of Arp3 is sufficient to rescue slowed comet tail speed and restrict spread. Importantly, ISG15-deficient neonatal mice have aberrant epidermal epithelia characterized by keratinocytes with diffuse cortical actin, which could underlie observed defects in wound healing in human patients who lack ISG15. Ultimately, our discovery links host innate immune responses to cytoskeletal dynamics with therapeutic implications for viral infection and metastasis.

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Avaliação PREreview de Craig McCormick

De autoria de Craig McCormick

We, the students of MICI5029/5049, a Graduate Level Molecular Pathogenesis Journal Club at Dalhousie University in Halifax, NS, Canada, hereby submit a review of the following BioRxiv preprint:

ISG15-modification of the Arp2/3 complex restricts pathogen spread Yifeng Zhang1, Brittany Ripley1, Wei…

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