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Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake

Author

Listed:
  • Arjen J. Jakobi

    (Structural and Computational Biology Unit
    European Molecular Biology Laboratory (EMBL), Hamburg Unit c/o DESY
    The Hamburg Centre for Ultrafast Imaging (CUI)
    Delft University of Technology)

  • Stefan T. Huber

    (Structural and Computational Biology Unit
    Delft University of Technology)

  • Simon A. Mortensen

    (Structural and Computational Biology Unit
    Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich
    JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich)

  • Sebastian W. Schultz

    (Oslo University Hospital, Montebello)

  • Anthimi Palara

    (University of Tromsø – The Arctic University of Norway)

  • Tanja Kuhm

    (Structural and Computational Biology Unit
    Delft University of Technology)

  • Birendra Kumar Shrestha

    (University of Tromsø – The Arctic University of Norway)

  • Trond Lamark

    (University of Tromsø – The Arctic University of Norway)

  • Wim J. H. Hagen

    (Structural and Computational Biology Unit)

  • Matthias Wilmanns

    (European Molecular Biology Laboratory (EMBL), Hamburg Unit c/o DESY
    The Hamburg Centre for Ultrafast Imaging (CUI))

  • Terje Johansen

    (University of Tromsø – The Arctic University of Norway)

  • Andreas Brech

    (Oslo University Hospital, Montebello)

  • Carsten Sachse

    (Structural and Computational Biology Unit
    Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich
    JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich)

Abstract

p62/SQSTM1 is an autophagy receptor and signaling adaptor with an N-terminal PB1 domain that forms the scaffold of phase-separated p62 bodies in the cell. The molecular determinants that govern PB1 domain filament formation in vitro remain to be determined and the role of p62 filaments inside the cell is currently unclear. We here determine four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of p62/SQSTM1 bodies using correlative cellular EM. We show that oligomerization or polymerization, driven by a double arginine finger in the PB1 domain, is a general requirement for lysosomal targeting of p62. Furthermore, the filamentous assembly state of p62 is required for autophagosomal processing of the p62-specific cargo KEAP1. Our results show that using such mechanisms, p62 filaments can be critical for cargo uptake in autophagy and are an integral part of phase-separated p62 bodies.

Suggested Citation

  • Arjen J. Jakobi & Stefan T. Huber & Simon A. Mortensen & Sebastian W. Schultz & Anthimi Palara & Tanja Kuhm & Birendra Kumar Shrestha & Trond Lamark & Wim J. H. Hagen & Matthias Wilmanns & Terje Johan, 2020. "Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14343-8
    DOI: 10.1038/s41467-020-14343-8
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