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Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons

Author

Listed:
  • Xiaoting Zhou

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Central South University)

  • You-Kyung Lee

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Xianting Li

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Henry Kim

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Carlos Sanchez-Priego

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Xian Han

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    University of Tennessee Health Science Center)

  • Haiyan Tan

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Suiping Zhou

    (St. Jude Children’s Research Hospital)

  • Yingxue Fu

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Kerry Purtell

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Qian Wang

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Gay R. Holstein

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Beisha Tang

    (Central South University
    Central South University)

  • Junmin Peng

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Nan Yang

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Zhenyu Yue

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.

Suggested Citation

  • Xiaoting Zhou & You-Kyung Lee & Xianting Li & Henry Kim & Carlos Sanchez-Priego & Xian Han & Haiyan Tan & Suiping Zhou & Yingxue Fu & Kerry Purtell & Qian Wang & Gay R. Holstein & Beisha Tang & Junmin, 2024. "Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47440-z
    DOI: 10.1038/s41467-024-47440-z
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