title: TRIM-directed selective autophagy regulates immune activation.
abstract: Selectivity of autophagy is achieved by target recognition; however, the number of autophagy receptors identified so far is limited. In this study we demonstrate that a subset of tripartite motif (TRIM) proteins mediate selective autophagy of key regulators of inflammatory signaling. MEFV/TRIM20, and TRIM21 act as autophagic receptors recognizing their cognate targets and delivering them for autophagic degradation. MEFV recognizes the inflammasome components NLRP3, CASP1 and NLRP1, whereas TRIM21 specifically recognizes the activated, dimeric from of IRF3 inducing type I interferon gene expression. MEFV and TRIM21 have a second activity, whereby they act not only as receptors but also recruit and organize key components of autophagic machinery consisting of ULK1, BECN1, ATG16L1, and mammalian homologs of Atg8, with a preference for GABARAP. MEFV capacity to organize the autophagy apparatus is affected by common mutations causing familial Mediterranean fever. These findings reveal a general mode of action of TRIMs as autophagic receptor-regulators performing a highly-selective type of autophagy (precision autophagy), with MEFV specializing in the suppression of inflammasome and CASP1 activation engendering IL1B/interleukin-1β production and implicated in the form of cell death termed pyroptosis, whereas TRIM21 dampens type I interferon responses.
authors.affiliation: a Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kimura
authors.affiliation: b Molecular Cancer Research Group , Institute of Medical Biology, University of Tromsø-The Arctic University of Norway , Tromsø , Norway.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.affiliation: a Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Choi
authors.affiliation: a Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mandell
authors.affiliation: b Molecular Cancer Research Group , Institute of Medical Biology, University of Tromsø-The Arctic University of Norway , Tromsø , Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.affiliation: a Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002352:Carrier Proteins / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D009154:Mutation / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta
keywords: BEC1; IRF3; ULK1; autophagy receptors; familial Mediterranean fever; inflammasome; interferon; interleukin-1β; tripartite motif class of proteins (TRIMs)