Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, up until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family and recognizes transmembrane proteins (i.e. cargos) having specific sorting signals in their cytosolic domains. Recent studies identified accessory proteins (tepsin, RUSC2 and the FHF complex) that co-operate with AP-4, and cargos (amyloid precursor protein, ATG9A and SERINC3/5) that are exported from the TGN in an AP-4-dependent manner. Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome formation and/or maturation. In addition, mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a form of complicated hereditary spastic paraplegia referred to as ‘AP-4-deficiency syndrome’ in humans. These findings demonstrated that mammalian AP-4 is required for the development and function of the central nervous system, possibly through its role in the sorting of ATG9A for the maintenance of autophagic homeostasis. In this article, we review the properties and functions of AP-4, and discuss how they might explain the clinical features of AP-4 deficiency.
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October 2020
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Cover Image
Centrosomes are microtubule-organizing centres required for the asymmetric division of neural stem cells, which support neurodevelopment, as discussed in a mini-review by Robinson and colleagues (pages 2101–2115) In the cover image, microtubules are shown in yellow and neural stem cells (aPKC) are magenta. Image provided by Dorothy Lerit.
Review Article|
October 21 2020
The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia
Juan S. Bonifacino
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Correspondence: Juan S. Bonifacino (juan.bonifacino@nih.gov)
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Publisher: Portland Press Ltd
Received:
July 09 2020
Revision Received:
September 22 2020
Accepted:
September 29 2020
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem Soc Trans (2020) 48 (5): 1877–1888.
Article history
Received:
July 09 2020
Revision Received:
September 22 2020
Accepted:
September 29 2020
Citation
Rafael Mattera, Raffaella De Pace, Juan S. Bonifacino; The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia. Biochem Soc Trans 30 October 2020; 48 (5): 1877–1888. doi: https://doi.org/10.1042/BST20190664
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