A Role for Cargo in Arf-dependent Adaptor Recruitment

Caster, Amanda H.; Sztul, Elizabeth; Kahn, Richard

doi:10.1074/jbc.m113.453621

Cited by 16 publications

(16 citation statements)

References 84 publications

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“…Recent studies suggest that cargo (the transmembrane proteins destined for packaging into vesicles) may confer specificity to the GEF recruitment/activation process. Expression of specific cargo proteins [furin, mannose-6-phosphate receptor (M6PR), and the amyloid precursor protein (APP)] and their arrest either at the Golgi, the TGN or endosomal membranes by experimental blocks resulted in an increased recruitment of ARF-dependent adaptors (AP-1, GGAs, and Mint3) in a cargo-dependent manner [92, 93]. Because adaptor recruitment is dependent on ARF activation, this model system reflects an indirect means of assessing the recruitment/activation of GEFs by the cargo.…”

Section: Role Of Lipids and Cargo In Gef Recruitmentmentioning

confidence: 99%

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Wright

Kahn

Sztul

2014

Cell. Mol. Life Sci.

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Eukaryotic cells require selective sorting and transport of cargo between intracellular compartments. This is accomplished at least in part by vesicles that bud from a donor compartment, sequestering a subset of resident protein “cargos” destined for transport to an acceptor compartment. A key step in vesicle formation and targeting is the recruitment of specific proteins that form a coat on the outside of the vesicle in a process requiring the activation of regulatory GTPases of the ARF family. Like all such GTPases, ARFs cycle between inactive, GDP-bound, and membrane-associated active, GTP-bound, conformations. And like most regulatory GTPases the activating step is slow and thought to be rate limiting in cells, requiring the use of ARF guanine nucleotide exchange factor (GEFs). ARF GEFs are characterized by the presence of a conserved, catalytic Sec7 domain, though they also contain motifs or additional domains that confer specificity to localization and regulation of activity. These domains have been used to define and classify five different sub-families of ARF GEFs. One of these, the BIG/GBF1 family, includes three proteins that are each key regulators of the secretory pathway. GEF activity initiates the coating of nascent vesicles via the localized generation of activated ARFs and thus these GEFs are the upstream regulators that define the site and timing of vesicle production. Paradoxically, while we have detailed molecular knowledge of how GEFs activate ARFs, we know very little about how GEFs are recruited and/or activated at the right time and place to initiate transport. This review summarizes the current knowledge of GEF regulation and explores the still uncertain mechanisms that position GEFs at “budding ready” membrane sites to generate highly localized activated ARFs.

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Section: Role Of Lipids and Cargo In Gef Recruitmentmentioning

confidence: 99%

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Wright

Kahn

Sztul

2014

Cell. Mol. Life Sci.

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“…AP-1 also has been shown to localize in the PNR encompassing TGN [65]. BFA is known to rapidly and reversibly inhibit the Arf-dependent recruitment of adaptors including AP-1 [33,34,[37][38][39]. The rapid reduction of colocalized AP-1 and LZTFL1 in the PNR upon the exposure to BFA and the recovery as early as 15 min after BFA removal indicate that both AP-1 and LZTFL1 are BFA sensitive Arf1-dependent adaptors.…”

Section: Discussionmentioning

confidence: 99%

“…Brefeldin A (BFA), a fungal metabolite that is known to inhibit guanine nucleotide exchange factors for Arf1, inactivate AP-1 and disturb the movement of newly synthesized proteins [33][34][35][36]. A short term (2 minute) treatment with BFA is known to rapidly and reversibly inhibit the Arf1-dependent recruitment of adaptins (AP-1, AP-2, AP-3 and AP-4) and has been successfully employed to study protein recruitment [33,34,[37][38][39]. HeLa cells treated with BFA for 2 minutes were either fixed or the drug was washed out, and the cells were allowed to recover for the times indicated, after which they were fixed and stained for LZTFL1, AP-1, and TGN marker p230.…”

Section: Ap-1 Dependent Localization Of Lztfl1 At Perinuclear Regionmentioning

confidence: 99%

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

Promchan

Natarajan

2020

PLoS ONE

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LZTFL1 participates in immune synapse formation, ciliogenesis, and the localization of ciliary proteins, and knockout of LZTFL1 induces abnormal distribution of heterotetrameric adaptor protein complex-1 (AP-1) in the Lztfl1-knockout mouse photoreceptor cells, suggesting that LZTFL1 is involved in intracellular transport. Here, we demonstrate that in vitro LZTFL1 directly binds to AP-1 and AP-2 and coimmunoprecipitates AP-1 and AP-2 from cell lysates. DxxFxxLxxxR motif of LZTFL1 is essential for these bindings, suggesting LZTFL1 has roles in AP-1 and AP-2-mediated protein trafficking. Since AP-1 and AP-2 are known to be involved in transferrin receptor 1 (TfR1) trafficking, the effect of LZTFL1 on TfR1 recycling was analyzed. TfR1, AP-1 and LZTFL1 from cell lysates could be coimmunoprecipitated. However, pull-down results indicate there is no direct interaction between TfR1 and LZTFL1, suggesting that LZTFL1 interaction with TfR1 is indirect through AP-1. We report the colocalization of LZTFL1 and AP-1, AP-1 and TfR1 as well as LZTFL1 and TfR1 in the perinuclear region (PNR) and the cytoplasm, suggesting a potential complex between LZTFL1, AP-1 and TfR1. The results from the disruption of adaptin recruitment with brefeldin A treatment suggested ADP-ribosylation factor-dependent localization of LZFL1 and AP-1 in the PNR. Knockdown of AP-1 reduces the level of LZTFL1 in the PNR, suggesting that AP-1 plays a role in LZTFL1 trafficking. Knockout of LZTFL1 reduces the cell surface level and the rate of internalization of TfR1, leading to a decrease of transferrin uptake, efflux, and internalization. However, knockout of LZTFL1 did not affect the cell surface levels of epidermal growth factor receptor and cation-independent mannose 6-phosphate receptor, indicating that LZTFL1 specifically regulates the cell surface level of TfR1. These data support a novel role of LZTFL1 in regulating the cell surface TfR1 level by interacting with AP-1 and AP-2.

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“…One of the outstanding questions in the regulation of Arf GTPases is the role of protein cargo in their activation. It has been proposed that the cargo acts upstream of Arf activation, in a manner analogous to the activation of heterotrimeric G-proteins by G-protein-coupled receptors (GPCRs) that serve as their GEFs, upon light or ligand stimulation (Caster et al, 2013). Although multiple Arf GEFs activate Arfs in spatiotemporally restricted manners, it is not clear what signals Arf GEFs recognize in order to activate Arfs.…”

Section: Introductionmentioning

confidence: 99%

“…Although multiple Arf GEFs activate Arfs in spatiotemporally restricted manners, it is not clear what signals Arf GEFs recognize in order to activate Arfs. The specific cargo has the capacity to regulate the Arf-dependent recruitment of the protein adaptors (Caster et al, 2013), which suggests that a functional complex between the cargo, the cognate Arf and an Arf GEF likely exists during membrane trafficking. However, currently the evidence for such a complex is absent.…”

Section: Introductionmentioning

confidence: 99%

The Arf GEF GBF1 and Arf4 synergize with the sensory receptor cargo, rhodopsin, to regulate ciliary membrane trafficking

Wang

Fresquez

Kandachar

et al. 2017

Journal of Cell Science

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The small GTPase Arf4 and the Arf GTPase-activating protein (GAP) ASAP1 cooperatively sequester sensory receptor cargo into transport carriers targeted to primary cilia, but the input that drives Arf4 activation in this process remains unknown. Here, we show, by using frog retinas and recombinant human proteins, that during the carrier biogenesis from the photoreceptor Golgi/trans-Golgi network (TGN) a functional complex is formed between Arf4, the Arf guanine nucleotide exchange factor (GEF) GBF1 and the light-sensing receptor, rhodopsin. Rhodopsin and Arf4 bind the regulatory Nterminal dimerization and cyclophillin-binding (DCB)-homology upstream of Sec7 (HUS) domain of GBF1. The complex is sensitive to Golgicide A (GCA), a selective inhibitor of GBF1 that accordingly blocks rhodopsin delivery to the cilia, without disrupting the photoreceptor Golgi. The emergence of newly synthesized rhodopsin in the endomembrane system is essential for GBF1-Arf4 complex formation in vivo. Notably, GBF1 interacts with the Arf GAP ASAP1 in a GCA-resistant manner. Our findings indicate that converging signals on GBF1 from the influx of cargo into the Golgi/ TGN and the feedback from Arf4, combined with input from ASAP1, control Arf4 activation during sensory membrane trafficking to primary cilia.

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A Role for Cargo in Arf-dependent Adaptor Recruitment

Cited by 16 publications

References 84 publications

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation

Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1

The Arf GEF GBF1 and Arf4 synergize with the sensory receptor cargo, rhodopsin, to regulate ciliary membrane trafficking

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