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TitleCombinatorial selective ER-phagy remodels the ER during neurogenesis.
Journal, issue, pagesNat Cell Biol, Vol. 26, Issue 3, Page 378-392, Year 2024
Publish dateMar 1, 2024
AuthorsMelissa J Hoyer / Cristina Capitanio / Ian R Smith / Julia C Paoli / Anna Bieber / Yizhi Jiang / Joao A Paulo / Miguel A Gonzalez-Lozano / Wolfgang Baumeister / Florian Wilfling / Brenda A Schulman / J Wade Harper /
PubMed AbstractThe endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle ...The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.
External linksNat Cell Biol / PubMed:38429475 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-19194: In situ cryo-electron tomogram of an autophagosome in the projection of an iPSC-derived neuron #2
Method: EM (tomography)

EMDB-19346: In situ cryo-electron tomogram of an autophagosome in the projection of an iPSC-derived neuron #1
Method: EM (tomography)

Source
  • Homo sapiens (human)

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