Suppressor of Cytokine Signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling
- The Walter and Eliza Hall Institute of Medical Research, Australia
- Hudson Institute of Medical Research, Australia
- The University of Newcastle, Australia
- Fudan University, China
- University of Melbourne, Australia
Abstract
Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) 5 has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
Article and author information
Author details
Sandra E Nicholson
Funding
National Health and Medical Research Council (Project grants #1047248,1045762,Program grant #1016647)
- Nicos A Nicola
- Philip M Hansbro
- Sandra E Nicholson
Victorian State Government, Australia (Operational Infrastructure Scheme grant)
- Lukasz Kedzierski
- Tatiana B Kolesnik
- Edmond M Linossi
- Laura Dagley
- Sarah Freeman
- Simon M Chatfield
- Nicholas Huntington
- Gabrielle Belz
- Andrew Webb
- Nicos A Nicola
- Sandra E Nicholson
Australian Research Council (Future Fellowship)
- Gabrielle Belz
Australian Federal Government (Australian Postgraduate Award)
- Edmond M Linossi
National Health and Medical Research Council (Fellowship)
- Michelle D Tate
- Nicos A Nicola
- Katherine Kedzierska
- Philip M Hansbro
National Health and Medical Research Council (IRIISS grant 361646)
- Lukasz Kedzierski
- Tatiana B Kolesnik
- Edmond M Linossi
- Laura Dagley
- Sarah Freeman
- Giuseppe Infusini
- Simon M Chatfield
- Nicholas Huntington
- Gabrielle Belz
- Andrew Webb
- Nicos A Nicola
- Sandra E Nicholson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments followed the NHMRC Code of Practice for the Care and Use of Animals for Scientific Purposes guidelines and were approved by the Walter and Eliza Hall Institute's Animal Ethics Committee (Ethics Number: 2014.029).
Human subjects: All subjects gave written informed consent and all procedures were performed according to approval from the University of Newcastle Human Ethics Committee (Ethics Number: H-163-1205).
Copyright
© 2017, Kedzierski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,518
- views
-
- 540
- downloads
-
- 62
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Suppressor of Cytokine Signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling
eLife 6:e20444.
https://doi.org/10.7554/eLife.20444
Further reading
-
- Cancer Biology
- Cell Biology
Understanding the cell cycle at the single-cell level is crucial for cellular biology and cancer research. While current methods using fluorescent markers have improved the study of adherent cells, non-adherent cells remain challenging. In this study, we addressed this gap by combining a specialized surface to enhance cell attachment, the FUCCI(CA)2 sensor, an automated image analysis pipeline, and a custom machine learning algorithm. This approach enabled precise measurement of cell cycle phase durations in non-adherent cells. This method was validated in acute myeloid leukemia cell lines NB4 and Kasumi-1, which have unique cell cycle characteristics, and we tested the impact of cell cycle-modulating drugs on NB4 cells. Our cell cycle analysis system, which is also compatible with adherent cells, is fully automated and freely available, providing detailed insights from hundreds of cells under various conditions. This report presents a valuable tool for advancing cancer research and drug development by enabling comprehensive, automated cell cycle analysis in both adherent and non-adherent cells.
-
- Cell Biology
The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulate and digestive lysosomes are rudimentary. Together, our results reveal an important and unexpected role of a deubiquitinating enzyme in endosome maturation.
