Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Autophagy. 2012 Mar;8(3):350-63. doi: 10.4161/auto.18806. Epub 2012 Mar 1.

Abstract

A significant portion of newly synthesized protein fails to fold properly and is quickly degraded. These defective ribosomal products (DRiPs) are substrates for the ubiquitin-proteasome system (UPS) and give rise to a large fraction of peptides presented by major histocompatibility complex class I molecules (MHCI). Here, we showed that DRiPs are also autophagy substrates, which accumulate upon autophagy inhibition in aggresome-like-induced structures (ALIS). Aggregation is critically depending on p62/SQSTM1, but occurs in the absence of activation of the NRF2 signaling axis and transcriptional regulation of p62/SQSTM1. We demonstrated that autophagy-targeted DRiPs can become UPS substrates and give rise to MHCI presented peptides upon autophagy inhibition. We further demonstrated that autophagy targeting of DRiPs is controlled by NBR1, but not p62/SQSTM1, CHIP or BAG-1. Active autophagy therefore directly modulates MHCI presentation by constantly degrading endogenous defective neosynthesized antigens, which are submitted to at least two distinct quality control mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Antigen Presentation / drug effects
  • Antigen Presentation / immunology*
  • Autophagy* / drug effects
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Inclusion Bodies / drug effects
  • Inclusion Bodies / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Protein Biosynthesis* / drug effects
  • Protein Folding / drug effects
  • Protein Processing, Post-Translational* / drug effects
  • Protein Structure, Quaternary
  • Proteins / metabolism
  • Proteolysis / drug effects
  • Puromycin / pharmacology
  • Recombinant Fusion Proteins / metabolism
  • Ribosomes / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction / drug effects
  • Substrate Specificity / drug effects
  • Transcription, Genetic / drug effects
  • Ubiquitin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Histocompatibility Antigens Class I
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • NBR1 protein, human
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proteasome Inhibitors
  • Proteins
  • Recombinant Fusion Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • Green Fluorescent Proteins
  • Puromycin
  • Proteasome Endopeptidase Complex