title: FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions.
abstract: Innate immune response plays a critical role in controlling invading pathogens, but such an immune response must be tightly regulated. Insufficient or overactivated immune responses may lead to harmful or even fatal consequences. To dissect the complex host-parasite interactions and the molecular mechanisms underlying innate immune responses to infections, here we investigate the role of FOS-like antigen 1 (FOSL1) in regulating the host type I interferon (IFN-I) response to malaria parasite and viral infections. FOSL1 is known as a component of a transcription factor but was recently implicated in regulating the IFN-I response to malaria parasite infection. Here we show that FOSL1 can act as a negative regulator of IFN-I signaling. Upon stimulation with poly(I:C), malaria parasite-infected red blood cells (iRBCs), or vesicular stomatitis virus (VSV), FOSL1 "translocated" from the nucleus to the cytoplasm, where it inhibited the interactions between TNF receptor-associated factor 3 (TRAF3), TIR domain-containing adapter inducing IFN-β (TRIF), and Tank-binding kinase 1 (TBK1) via impairing K63-linked polyubiquitination of TRAF3 and TRIF. Importantly, FOSL1 knockout chimeric mice had lower levels of malaria parasitemia or VSV titers in peripheral blood and decreased mortality compared with wild-type (WT) mice. Thus, our findings have identified a new role for FOSL1 in negatively regulating the host IFN-I response to malaria and viral infections and have identified a potential drug target for controlling malaria and other diseases.
  
  
  
  Infections of pathogens can trigger vigorous host immune responses, including activation and production of type I interferon (IFN-I). In this study, we investigated the role of FOSL1, a molecule previously known as a transcription factor, in negatively regulating IFN-I responses to malaria and viral infections. We showed that FOSL1 was upregulated and translocated into the cytoplasm of cells after stimulation for IFN-I production. FOSL1 could affect TRAF3 and TRIF ubiquitination and consequently impaired the association of TRAF3, TRIF, and TBK1, leading to inhibition of IFN-I signaling. In vivo experiments with FOSL1 knockout chimeric mice further validated the negative role of FOSL1 in IFN-I production and antimicrobial responses. This report reveals a new functional role for FOSL1 in IFN-I signaling and dissects the mechanism by which FOSL1 regulates IFN-I responses to malaria and viral infections, which can be explored as a potential drug target for disease control and management.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, People's Republic of China.|Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Baowei
authors.initials: B
authors.lastname: Cai
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, People's Republic of China xsu@niaid.nih.gov rwang3@tmhs.org.|Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA xsu@niaid.nih.gov rwang3@tmhs.org.|Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, New York, USA.|Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, Texas, USA.
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Wang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D008288:Malaria / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D059208:Parasite Load; D010961:Plasmodium / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000378:metabolism*; D018353:Rhabdoviridae Infections / Q000276:immunology; D016019:Survival Analysis; D048008:TNF Receptor-Associated Factor 3 / Q000037:antagonists & inhibitors*; D018116:Vesiculovirus / Q000276:immunology*; D019562:Viral Load; D000099169:Fos-Related Antigen 1
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D011070:Poly I-C; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D048008:TNF Receptor-Associated Factor 3; D000099169:Fos-Related Antigen 1; C476286:Ticam1 protein, mouse; C498588:Tbk1 protein, mouse