title: The ubiquitin-like protein PLIC-1 or ubiquilin 1 inhibits TLR3-Trif signaling.
abstract: BACKGROUND
  The innate immune responses to virus infection are initiated by either Toll-like receptors (TLR3/7/8/9) or cytoplasmic double-stranded RNA (dsRNA)-recognizing RNA helicases RIG-I and MDA5. To avoid causing injury to the host, these signaling pathways must be switched off in time by negative regulators.
  
  
  RESULTS
  Through yeast-two hybrid screening, we found that an ubiquitin-like protein named protein linking integrin-associated protein to cytoskeleton 1(PLIC-1 or Ubiquilin 1) interacted with the Toll/interleukin-1 receptor (TIR) domain of TLR4. Interestingly, PLIC-1 had modest effect on TLR4-mediated signaling, but strongly suppressed the transcriptional activation of IFN-β promoter through the TLR3-Trif-dependent pathway. Concomitantly, reduction of endogenous PLIC-1 by short-hairpin interfering RNA (shRNA) enhanced TLR3 activation both in luciferase reporter assays as well as in new castle disease virus (NDV) infected cells. An interaction between PLIC-1 and Trif was confirmed in co-immunoprecipitation (Co-IP) and GST-pull-down assays. Subsequent confocal microscopic analysis revealed that PLIC-1 and Trif colocalized with the autophagosome marker LC3 in punctate subcellular structures. Finally, overexpression of PLIC-1 decreased Trif protein abundance in a Nocodazole-sensitive manner.
  
  
  CONCLUSIONS
  Our results suggest that PLIC-1 is a novel inhibitor of the TLR3-Trif antiviral pathway by reducing the abundance of Trif.
authors.affiliation: Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Biswas
authors.forename: Shufeng
authors.initials: S
authors.lastname: Liu
authors.forename: Tapani
authors.initials: T
authors.lastname: Ronni
authors.forename: Steven E
authors.initials: SE
authors.lastname: Aussenberg
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009522:Newcastle disease virus / Q000187:drug effects / Q000502:physiology; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C505371:MAVS protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C107792:UBQLN1 protein, human; D016899:Interferon-beta; D008156:Luciferases; D011070:Poly I-C