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Cited by 154Cellular transport and secretionBiotin and Related StudiesAutophagy in Disease and Therapy

Distinct and Overlapping Roles for AP-1 and GGAs Revealed by the “Knocksideways” System

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Hirst, Jennifer, Borner, Georg H.H., Antrobus, Robin, Peden, Andrew A., Hodson, Nicola A., Sahlender, Daniela A., Robinson, Margaret S.·2012·Current Biology
DOI 10.1016/j.cub.2012.07.012PMC PMC3485558
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Abstract

Although adaptor protein complex 1 (AP-1) and Golgi-localized, γ ear-containing, ADP-ribosylation factor-binding proteins (GGAs) are both adaptors for clathrin-mediated intracellular trafficking, the pathways they mediate and their relationship to each other remain open questions. To tease apart the functions of AP-1 and GGAs, we rapidly inactivated each adaptor using the "knocksideways" system and then compared the protein composition of clathrin-coated vesicle (CCV) fractions from control and knocksideways cells. The AP-1 knocksideways resulted in a dramatic and unexpected loss of GGA2 from CCVs. Over 30 other peripheral membrane proteins and over 30 transmembrane proteins were also depleted, including several mutated in genetic disorders, indicating that AP-1 acts as a linchpin for intracellular CCV formation. In contrast, the GGA2 knocksideways affected only lysosomal hydrolases and their receptors. We propose that there are at least two populations of intracellular CCVs: one containing both GGAs and AP-1 for anterograde trafficking and another containing AP-1 for retrograde trafficking. Our study shows that knocksideways and proteomics are a powerful combination for investigating protein function, which can potentially be used on many different types of proteins.

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  • GGA proteins are recruited to TGN by Arf1 and function cooperatively with AP-1 to regulate trafficking of cargoes from TGN to endosomes.

    “The GGA proteins, which are also recruited to the TGN by Arf1, have been shown to function cooperatively with AP-1 to regulate the trafficking of cargoes from the TGN to the endosomes (Doray et al., 2002; Hirst et al., 2012).”

    From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Hirst et al., 2012

    In the Conclusions, the paper proposes that GGAs act with AP-1 to move hydrolase–receptor complexes from a TGN/post-TGN compartment toward endosomes. The Coat Components and Accessory Factors section says ARF1 facilitates GGA recruitment onto membranes, and the Conclusions place GGAs mainly at the TGN. The claim is stronger and broader than the paper on cooperation: it says this function has been shown for cargoes generally, whereas the paper presents it as a proposal focused on hydrolase–receptor complexes. (LLM, conf=0.84)

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Research works printed but not linked: 29

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Authors
Hirst, J., Borner, G. H. H., Antrobus, R., Peden, A. A., Hodson, N. A., Sahlender, D. A., & Robinson, M. S.
Affiliations
University of Cambridge (GB)
Corresponding author
  • Hirst, Jennifer
  • Robinson, Margaret S.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2012-09
Volume
22
Issue
18
Pages
1711-1716
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2012.07.012
PMC
PMC3485558
OpenAlex
W2154083208
Cited by
154
References
0
Citations by year
2026: 7 · 2025: 4 · 2024: 13 · 2023: 7 · 2022: 13 · 2021: 10 · 2020: 7 · 2019: 19 · 2018: 16 · 2017: 4 · 2016: 9 · 2015: 15 · 2014: 19 · 2013: 10 · 2012: 1
FWCI
6.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
GGA2, clathrin-coated vesicles, anterograde trafficking, retrograde trafficking, lysosomal enzymes, peripheral membrane proteins, transmembrane proteins
MeSH terms
Clathrin, HeLa Cells, Humans, Protein Binding, Clathrin-Coated Vesicles, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport, Adaptor Protein Complex 1, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, SNARE Proteins, R-SNARE Proteins

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