Fu, BishiWang, LingyanLi, ShitaoDorf, Martin2017-12-062017Fu, Bishi, Lingyan Wang, Shitao Li, and Martin E. Dorf. 2017. “ZMPSTE24 defends against influenza and other pathogenic viruses.” The Journal of Experimental Medicine 214 (4): 919-929. doi:10.1084/jem.20161270. http://dx.doi.org/10.1084/jem.20161270.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492386Zinc metallopeptidase STE24 (ZMPSTE24) is a transmembrane metalloprotease whose catalytic activity is critical for processing lamin A on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. We now report ZMPSTE24 is a virus-specific effector that restricts enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia, but not murine leukemia or adenovirus. ZMPSTE24-mediated antiviral action is independent of protease activity. Coimmunoprecipitation studies indicate ZMPSTE24 can complex with proteins of the interferon-induced transmembrane protein (IFITM) family. IFITM proteins impede viral entry, and ZMPSTE24 expression is necessary for IFITM antiviral activity. In vivo studies demonstrate ZMPSTE24-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. Collectively, these findings identify ZMPSTE24 as an intrinsic broad-spectrum antiviral protein and provide insights into antiviral defense mechanisms.en-USBrief Definitive ReportJournal Article2017-12-0610.1084/jem.20161270