title: TAX1BP1 Restrains Virus-Induced Apoptosis by Facilitating Itch-Mediated Degradation of the Mitochondrial Adaptor MAVS.
abstract: The host response to RNA virus infection consists of an intrinsic innate immune response and the induction of apoptosis as mechanisms to restrict viral replication. The mitochondrial adaptor molecule MAVS plays critical roles in coordinating both virus-induced type I interferon production and apoptosis; however, the regulation of MAVS-mediated apoptosis is poorly understood. Here, we show that the adaptor protein TAX1BP1 functions as a negative regulator of virus-induced apoptosis. TAX1BP1-deficient cells are highly sensitive to apoptosis in response to infection with the RNA viruses vesicular stomatitis virus and Sendai virus and to transfection with poly(I·C). TAX1BP1 undergoes degradation during RNA virus infection, and loss of TAX1BP1 is associated with apoptotic cell death. TAX1BP1 deficiency augments virus-induced activation of proapoptotic c-Jun N-terminal kinase (JNK) signaling. Virus infection promotes the mitochondrial localization of TAX1BP1 and concomitant interaction with the mitochondrial adaptor MAVS. TAX1BP1 recruits the E3 ligase Itch to MAVS to trigger its ubiquitination and degradation, and loss of TAX1BP1 or Itch results in increased MAVS protein expression. Together, these results indicate that TAX1BP1 functions as an adaptor molecule for Itch to target MAVS during RNA virus infection and thus restrict virus-induced apoptosis.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA ychoi15@jhmi.edu eharhaj1@jhmi.edu.
authors.forename: Young Bong
authors.identifier: http://orcid.org/0000-0002-2523-1441
authors.initials: YB
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Noula
authors.initials: N
authors.lastname: Shembade
authors.affiliation: Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Kislay
authors.initials: K
authors.lastname: Parvatiyar
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA ychoi15@jhmi.edu eharhaj1@jhmi.edu.
authors.forename: Edward William
authors.initials: EW
authors.lastname: Harhaj
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D012328:RNA Viruses / Q000472:pathogenicity*; D012097:Repressor Proteins / Q000378:metabolism*; D029082:Sendai virus / Q000472:pathogenicity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D018116:Vesiculovirus / Q000472:pathogenicity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C505371:MAVS protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C120635:TAX1BP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Itch; MAVS; RNA viruses; TAX1BP1; innate immunity; ubiquitination