Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction.
Cellular protein interaction networks are integral to host defence and immune signalling pathways, which are often hijacked by viruses via protein interactions. However, the comparative virus-host protein interaction networks and how these networks control host immunity and viral infection remain to be elucidated. Here, we mapped protein interactomes between human host and several influenza A viruses (IAV). Comparative analyses of the interactomes identified common and unique interaction patterns regulating innate immunity and viral infection. Functional screening of the 'core' interactome consisting of common interactions identified five novel host factors regulating viral infection. Plakophilin 2 (PKP2), an influenza PB1-interacting protein, restricts IAV replication and competes with PB2 for PB1 binding. The binding competition leads to perturbation of the IAV polymerase complex, thereby limiting polymerase activity and subsequent viral replication. Taken together, comparative analyses of the influenza-host protein interactomes identified PKP2 as a natural inhibitor of IAV polymerase complex.
Department of Physiological Sciences, Oklahoma State University, 264 McELroy Hall, Stillwater, Oklahoma 74078, USA.
Lingyan
L
Wang
Department of Microbiology &Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, NRB830, Boston, Massachusetts 02115, USA.
Bishi
B
Fu
School of Stomatology, Peking University, 22 Zhongguancun South Avenue, Beijing 100081, China.
Wenjun
W
Li
Department of Physiological Sciences, Oklahoma State University, 264 McELroy Hall, Stillwater, Oklahoma 74078, USA.
Girish
G
Patil
Department of Physiological Sciences, Oklahoma State University, 264 McELroy Hall, Stillwater, Oklahoma 74078, USA.
Lin
0000-0002-4811-4897
L
Liu
Department of Microbiology &Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, NRB830, Boston, Massachusetts 02115, USA.
Martin E
ME
Dorf
Department of Physiological Sciences, Oklahoma State University, 264 McELroy Hall, Stillwater, Oklahoma 74078, USA.
Shitao
S
Li
D000818:Animals; D004285:Dogs; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D051191:Plakophilins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D060066:Protein Interaction Maps / Q000276:immunology; D034741:RNA, Small Interfering / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology
C057027:PB2 protein, Influenzavirus A; C495337:PKP2 protein, human; D051191:Plakophilins; D034741:RNA, Small Interfering; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase