p62 filaments capture and present ubiquitinated cargos for autophagy

• Gabriele Zaffagnini ^[1] ; Adriana Savova ^[1] ; Alberto Danieli ^[1] ; Julia Romanov ^[1] ; Shirley Tremel ^[2] ; Michael Ebner ^[1] ; Thomas Peterbauer ^[1] ; Martin Sztacho ^[5] ; Riccardo Trapannone ^[1] ; Abul K Tarafder ^[3] ; Carsten Sachse ^[4] ; Sascha Martens ^[1]
  1. [1] University of Vienna

     University of Vienna

     Innere Stadt, Austria

     
  2. [2] MRC Laboratory of Molecular Biology

     MRC Laboratory of Molecular Biology

     Cambridge District, Reino Unido

     
  3. [3] 2 Structural and Computational Biology Unit European Molecular Biology Laboratory Heidelberg Germany; 7Present address: Sir William Dunn School of Pathology University of Oxford Oxford UK
  4. [4] 2 Structural and Computational Biology Unit European Molecular Biology Laboratory Heidelberg Germany
  5. [5] 1 Department of Biochemistry and Cell Biology Max F. Perutz Laboratories (MFPL) Vienna Biocenter (VBC) University of Vienna Vienna Austria; 6Present address: Institute of Molecular Genetics Prague 4 Czech Republic

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 5, 2018
• Idioma: inglés
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  • The removal of misfolded, ubiquitinated proteins is an essential part of the protein quality control. The ubiquitin‐proteasome system (UPS) and autophagy are two interconnected pathways that mediate the degradation of such proteins. During autophagy, ubiquitinated proteins are clustered in a p62‐dependent manner and are subsequently engulfed by autophagosomes. However, the nature of the protein substrates targeted for autophagy is unclear. Here, we developed a reconstituted system using purified components and show that p62 and ubiquitinated proteins spontaneously coalesce into larger clusters. Efficient cluster formation requires substrates modified with at least two ubiquitin chains longer than three moieties and is based on p62 filaments cross‐linked by the substrates. The reaction is inhibited by free ubiquitin, K48‐, and K63‐linked ubiquitin chains, as well as by the autophagosomal marker LC3B, suggesting a tight cross talk with general proteostasis and autophagosome formation. Our study provides mechanistic insights on how substrates are channeled into autophagy.