E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3 (PLoS Pathog 11(8):e1005095, 2015)

報告日期: 2015/10/13
報告時間: 4:00/4:50
報告學生: 洪呈輝
講評老師: 張堯
附件下載: 下載[1500-1443053396-1.pdf] 

E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3

Nicholas M. Chesarino, et al. (2015). PLOS Pathogens 11(8): e1005095

Speaker: Chen-Huei Hung (洪呈輝)          Time: 16:10-16:50, Oct. 13, 2015

Commentator: Dr. Yao Chang (張堯)       Place: Room 602

Abstract:

Interferon-induced transmembrane protein 3 (IFITM3) restricts cellular infection by several medically important viruses including all strains of influenza virus that have been tested to date[1]. IFITM3 is present at low levels within most cells at steady state and is induced by interferons only after infection. The inability to up-regulate IFITM3 levels independently of infection or interferons is a challenge harnessing the activity of IFITM3. A non-ubiquitinated mutant of IFITM3 possessed enhanced antiviral activity and a longer half-life as compared to wild type IFITM3[2] , indicating that inhibition of IFITM3 ubiquitination could augment the activity and/or levels of endogenous IFITM3, thus offering a strategy for exploiting IFITM3. The authors demonstrated that the E3 ubiquitin ligase NEDD4 ubiquitinates IFITM3 in cells and in vitro. The IFITM3 ubiquitination is dependent upon the presence of a PPxY motif within IFITM3 and the WW domain-containing region of NEDD4, and NEDD4 decreases baseline IFITM3 levels by ubiquitinating IFITM3 and promoting its turnover. Depletion of NEDD4 in cells results in IFITM3 accumulation and greater resistance to infection by influenza viruses. They also investigated that the steady state turnover of IFITM3 occurs through the lysosomal degradation pathway. Therefore, NEDD4 was identified as a regulator of IFITM3 levels and as a novel drug target for preventing influenza virus and other viruses sensitive to IFITM3.

References:

  1. Huang, I.C., et al., Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog, 2011. 7(1): p. e1001258.
  2. Yount, J.S., R.A. Karssemeijer, and H.C. Hang, S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. J Biol Chem, 2012. 287(23): p. 19631-41.