title: Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation.
abstract: Pathogens and cellular danger signals activate sensors such as RIG-I and NLRP3 to produce robust immune and inflammatory responses through respective adaptor proteins MAVS and ASC, which harbor essential N-terminal CARD and PYRIN domains, respectively. Here, we show that CARD and PYRIN function as bona fide prions in yeast and that their prion forms are inducible by their respective upstream activators. Likewise, a yeast prion domain can functionally replace CARD and PYRIN in mammalian cell signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, a conserved fungal NOD-like receptor and prion pair can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jueqi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Siqi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qiu-Xing
authors.initials: QX
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: randal.halfmann@utsouthwestern.edu.
authors.forename: Randal
authors.initials: R
authors.lastname: Halfmann
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: zhijian.chen@utsouthwestern.edu.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D005075:Biological Evolution; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058105:Polymerization; D011328:Prions / Q000378:metabolism*; D015398:Signal Transduction; D015003:Yeasts / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011328:Prions; C512612:MAVS protein, mouse; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse