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ISG15-modification of the Arp2/3 complex restricts pathogen spread
ISG15-modification of the Arp2/3 complex restricts pathogen spread
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Length:
20 minutes
Released:
Dec 27, 2022
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.27.522022v1?rss=1
Authors: Zhang, Y., Ripley, B. M., Ouyang, W., Sturtz, M., Upton, E., Luhmann, E., Vessely, M., Coloma, R., Schwery, N., Anthony, S. M., Goeken, A., Moninger, T. O., Harty, J. T., Klingelhutz, A. J., Lundberg, E., Meyerholz, D. K., Manicassamy, B., Stipp, C. S., Guerra, S., Radoshevich, L.
Abstract:
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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http://biorxiv.org/cgi/content/short/2022.12.27.522022v1?rss=1
Authors: Zhang, Y., Ripley, B. M., Ouyang, W., Sturtz, M., Upton, E., Luhmann, E., Vessely, M., Coloma, R., Schwery, N., Anthony, S. M., Goeken, A., Moninger, T. O., Harty, J. T., Klingelhutz, A. J., Lundberg, E., Meyerholz, D. K., Manicassamy, B., Stipp, C. S., Guerra, S., Radoshevich, L.
Abstract:
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.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Dec 27, 2022
Format:
Podcast episode
Titles in the series (100)
Uterine histotroph and conceptus development. III. Adrenomedullin stimulates proliferation, migration and adhesion of porcine trophectoderm cells via AKT-TSC2-MTOR cell signaling pathway. by PaperPlayer biorxiv cell biology