title: ZMPSTE24 defends against influenza and other pathogenic viruses.
abstract: Zinc 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.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Bishi
authors.identifier: 0000-0002-1524-3991
authors.initials: B
authors.lastname: Fu
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078 dorf@hms.harvard.edu shitao.li@okstate.edu.
authors.forename: Shitao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 dorf@hms.harvard.edu shitao.li@okstate.edu.
authors.forename: Martin E
authors.identifier: 0000-0001-9787-6487
authors.initials: ME
authors.lastname: Dorf
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D007251:Influenza, Human / Q000517:prevention & control*; D008565:Membrane Proteins / Q000502:physiology*; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014777:Virus Diseases / Q000517:prevention & control*
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D008565:Membrane Proteins; C062010:leu-13 antigen; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; C120130:ZMPSTE24 protein, human