title: Influenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins.
abstract: The ubiquitin-like protein ISG15 and its conjugation to proteins (ISGylation) are strongly induced by type I interferon. Influenza B virus encodes non-structural protein 1 (NS1B) that binds human ISG15 and provides an appropriate model for determining how ISGylation affects virus replication in human cells. Here using a recombinant virus encoding a NS1B protein defective in ISG15 binding, we show that NS1B counteracts ISGylation-mediated antiviral activity by binding and sequestering ISGylated viral proteins, primarily ISGylated viral nucleoprotein (NP), in infected cells. ISGylated NP that is not sequestered by mutant NS1B acts as a dominant-negative inhibitor of oligomerization of the more abundant unconjugated NP. Consequently formation of viral ribonucleoproteins that catalyse viral RNA synthesis is inhibited, causing decreased viral protein synthesis and virus replication. We verify that ISGylated NP is largely responsible for inhibition of viral RNA synthesis by generating recombinant viruses that lack known ISGylation sites in NP.
authors: Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors: Chen
authors: C
authors: Zhao
authors: Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors: Haripriya
authors: H
authors: Sridharan
authors: Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors: Ran
authors: R
authors: Chen
authors: Biogen, Inc., Cambridge, Massachusetts 02142, USA.
authors: Darren P
authors: DP
authors: Baker
authors: Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors: Shanshan
authors: S
authors: Wang
authors: Department of Molecular Biosciences, Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors: Robert M
authors: RM
authors: Krug
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D010450:Endopeptidases / Q000235:genetics; D006801:Humans; D009981:Influenza B virus / Q000235:genetics / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis* / Q000235:genetics; D012261:Ribonucleoproteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: D016207:Cytokines; C085820:INS1 protein, influenza virus; D034741:RNA, Small Interfering; D012367:RNA, Viral; D012261:Ribonucleoproteins; D014452:Ubiquitins; D017361:Viral Nonstructural Proteins; C074034:ISG15 protein, human; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase