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

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.

SUBMITTER: Zhou X

PROVIDER: S-EPMC11006854 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Zhou Xiaoting X Lee You-Kyung YK Li Xianting X Kim Henry H Sanchez-Priego Carlos C Han Xian X Tan Haiyan H Zhou Suiping S Fu Yingxue Y Purtell Kerry K Wang Qian Q Holstein Gay R GR Tang Beisha B Peng Junmin J Yang Nan N Yue Zhenyu Z

Nature communications 20240410 1

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 reve ...[more]

PMID: 38600097

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Project description:Epilepsy encompasses a spectrum of chronic brain disorders characterized by transient central nervous system dysfunctions induced by recurrent, aberrant, synchronized neuronal discharges. Hippocampal sclerosis (HS) is identified as the predominant pathological alteration in epilepsy, particularly in temporal lobe epilepsy. This study investigates the metabolic profiles of epileptic hippocampal tissues using proteomics and lipidomics techniques. An epilepsy model was established in Sprague-Dawley (SD) rats via intraperitoneal injection of pentylenetetrazole (PTZ), with hippocampal tissue samples subsequently extracted for histopathological examination. Proteomics analysis was conducted using isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), while lipidomics analysis employed ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC Q-TOF/MS). Proteomic analysis identified 144 proteins with significant differential expression in acute epileptic hippocampal tissue and 83 proteins in chronic epileptic hippocampal tissue. Key proteins, including neurofilament heavy (Nefh), vimentin (Vim), gelsolin (Gsn), NAD-dependent protein deacetylase (Sirt2), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (Cnp), myocyte enhancer factor 2D (Mef2d), and Cathepsin D (Ctsd), were pivotal in epileptic hippocampal tissue injury and validated through parallel reaction monitoring (PRM). Concurrently, lipid metabolomics analysis identified 32 metabolites with significant differential expression in acute epileptic hippocampal tissue and 61 metabolites in chronic epileptic hippocampal tissue. Bioinformatics analysis indicated that glycerophospholipid (GP) metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and glycerolipid (GL) metabolism were crucial in epileptic hippocampal tissue injury. Integrated proteomics and lipidomics analysis revealed key protein-lipid interactions in acute and chronic epilepsy and identified critical pathways such as sphingolipid signaling, autophagy, and calcium signaling. These findings provide deeper insights into the pathophysiological mechanisms of epileptic hippocampal tissue damage, potentially unveiling novel therapeutic avenues for clinicians.

Dataset Information

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

Publications

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

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