NEDD4 hampers combat of Influenza virus infections
Influenza virus causes many severe and debilitating infections every year making it a worldwide health concern. In both humans and mice, interferon-induced transmembrane protein 3 (IFITM3) is known to play a critical role in the combat of Influenza virus infections. Furthermore, levels of IFITM3 in the cell have been shown to be regulated in part by its ubiquitination, which targets the protein for degradation.
Recent research conducted by Chesarino, McMichael and Yount has identified NEDD4, an E3 ligase, as the protein responsible for ubiquitin modification of IFITM3. In addition, the authors show that this specific ubiquitination event relies upon the presence of the PPxY motif in IFITM3 and a WW domain containing region within NEDD4 itself. As expected, NEDD4 knockout mouse embryonic fibroblasts show defective ubiquitination of IFITM3 and subsequent accumulation of the protein. Strikingly, accumulation of IFITM3 in these cells confers increased resistance to infection by both Influenza virus A and Influenza virus B. This protective effect was also demonstrated in human lung cells that were knocked down for NEDD4 expression.
Complimentary to these findings, earlier studies identified that IFITM3 knockout mice succumb very readily when exposed to sub-lethal doses of influenza virus. In addition, possession of a particular genetic polymorphism in the human IFITM3 gene has been linked to increased severity of Influenza virus infection. Therefore, identification of NEDD4 as a regulator of IFITM3 turnover in this work highlights the value in future investigation of this ubiquitin ligase as a suitable drug target for the development of new therapeutic agents that could provide significant protection against Influenza virus infections in the future.
Original paper: E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing
Levels of the Antiviral Protein IFITM3. Nicholas M. Chesarino, Temet M. McMichael and Jacob S. Yount. PLOS Pathogens | DOI:10.1371/journal.ppat.1005095 August 11, 2015.
Image source: “EM of influenza virus” by Photo Credit: Cynthia GoldsmithContent Providers(s): CDC/ Dr. Terrence Tumpey – This media comes from the Centers for Disease Control and Prevention’s Public Health Image Library (PHIL), with identification number #8160. Licensed under Public Domain via Commons: https://commons.wikimedia.org/wiki/File:EM_of_influenza_virus.jpg#/media/File:EM_of_influenza_virus.jpg
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