TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

J Cell Biol. 2015 Sep 14;210(6):973-89. doi: 10.1083/jcb.201503023.

Abstract

The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy* / drug effects
  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Protein-1 Homolog
  • Beclin-1
  • Cytoplasm / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / immunology
  • Cytoskeletal Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate* / drug effects
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-gamma / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Microfilament Proteins / metabolism
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrin
  • RNA Interference
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / immunology
  • Ribonucleoproteins / metabolism*
  • Signal Transduction
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 8 Family
  • BECN1 protein, human
  • Beclin-1
  • Cytoskeletal Proteins
  • GABARAPL2 protein, human
  • IRF3 protein, human
  • Inflammasomes
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • MEFV protein, human
  • Membrane Proteins
  • Microfilament Proteins
  • Pyrin
  • Ribonucleoproteins
  • SS-A antigen
  • Interferon-gamma
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human