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ZZ-dependent regulation of p62/SQSTM1 in autophagy

Author

Listed:
  • Yi Zhang

    (University of Colorado School of Medicine)

  • Su Ran Mun

    (Seoul National University)

  • Juan F. Linares

    (Sanford Burnham Prebys Medical Discovery Institute)

  • JaeWoo Ahn

    (University of Colorado School of Medicine)

  • Christina G. Towers

    (University of Colorado School of Medicine)

  • Chang Hoon Ji

    (Seoul National University)

  • Brent E. Fitzwalter

    (University of Colorado School of Medicine)

  • Michael R. Holden

    (University of Colorado School of Medicine)

  • Wenyi Mi

    (Van Andel Research Institute)

  • Xiaobing Shi

    (Van Andel Research Institute)

  • Jorge Moscat

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Andrew Thorburn

    (University of Colorado School of Medicine)

  • Maria T. Diaz-Meco

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Yong Tae Kwon

    (Seoul National University
    Protech Inc.)

  • Tatiana G. Kutateladze

    (University of Colorado School of Medicine)

Abstract

Autophagic receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly deregulated in human diseases. The diverse functions of p62 arise from its ability to interact with a large set of ligands, such as arginylated (Nt-R) substrates. Here, we describe the structural mechanism for selective recognition of Nt-R by the ZZ domain of p62 (p62ZZ). We show that binding of p62ZZ to Nt-R substrates stimulates p62 aggregation and macroautophagy and is required for autophagic targeting of p62. p62 is essential for mTORC1 activation in response to arginine, but it is not a direct sensor of free arginine in the mTORC1 pathway. We identified a regulatory linker (RL) region in p62 that binds p62ZZ in vitro and may modulate p62 function. Our findings shed new light on the mechanistic and functional significance of the major cytosolic adaptor protein p62 in two fundamental signaling pathways.

Suggested Citation

  • Yi Zhang & Su Ran Mun & Juan F. Linares & JaeWoo Ahn & Christina G. Towers & Chang Hoon Ji & Brent E. Fitzwalter & Michael R. Holden & Wenyi Mi & Xiaobing Shi & Jorge Moscat & Andrew Thorburn & Maria , 2018. "ZZ-dependent regulation of p62/SQSTM1 in autophagy," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06878-8
    DOI: 10.1038/s41467-018-06878-8
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    Cited by:

    1. Thilini Abeywansha & Wei Huang & Xuan Ye & Allison Nawrocki & Xin Lan & Eckhard Jankowsky & Derek J. Taylor & Yi Zhang, 2023. "The structural basis of tRNA recognition by arginyl-tRNA-protein transferase," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xin Lan & Wei Huang & Su Bin Kim & Dechen Fu & Thilini Abeywansha & Jiemin Lou & Udayakumaran Balamurugan & Yong Tae Kwon & Chang Hoon Ji & Derek J. Taylor & Yi Zhang, 2024. "Oligomerization and a distinct tRNA-binding loop are important regulators of human arginyl-transferase function," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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