Adaptor protein complexes and intracellular transport

Park, Soo‐Jin; Guo, Xiaoli

doi:10.1042/bsr20140069

Cited by 146 publications

(186 citation statements)

References 85 publications

(88 reference statements)

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“…4F to H). In contrast, depletion of AP1M1, AP1M2, and AP4M1, the subunits of the adaptor protein complexes AP-1A, AP-1B, and AP-4, respectively, which sort in the secretory but not endocytic pathway (93), had no effect on HCVpp entry (Fig. 4F to H).…”

Section: Aak1mentioning

confidence: 81%

AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets

Neveu

Ziv-Av

Barouch-Bentov

et al. 2015

J Virol

110

155

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Hepatitis C virus (HCV) enters its target cell via clathrin-mediated endocytosis. AP-2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) are host kinases that regulate clathrin adaptor protein (AP)-mediated trafficking in the endocytic and secretory pathways. We previously reported that AAK1 and GAK regulate HCV assembly by stimulating binding of the subunit of AP-2, AP2M1, to HCV core protein. We also discovered that AAK1 and GAK inhibitors, including the approved anticancer drugs sunitinib and erlotinib, could block HCV assembly. Here, we hypothesized that AAK1 and GAK regulate HCV entry independently of their effect on HCV assembly. Indeed, silencing AAK1 and GAK expression inhibited entry of pseudoparticles and cell culture grown-HCV and internalization of Dil-labeled HCV particles with no effect on HCV attachment or RNA replication. AAK1 or GAK depletion impaired epidermal growth factor (EGF)-mediated enhanced HCV entry and endocytosis of EGF receptor (EGFR), an HCV entry cofactor and erlotinib's cancer target. Moreover, either RNA interference-mediated depletion of AP2M1 or NUMB, each a substrate of AAK1 and/or GAK, or overexpression of either an AP2M1 or NUMB phosphorylation site mutant inhibited HCV entry. Last, in addition to affecting assembly, sunitinib and erlotinib inhibited HCV entry at a postbinding step, their combination was synergistic, and their antiviral effect was reversed by either AAK1 or GAK overexpression. Together, these results validate AAK1 and GAK as critical regulators of HCV entry that function in part by activating EGFR, AP2M1, and NUMB and as the molecular targets underlying the antiviral effect of sunitinib and erlotinib (in addition to EGFR), respectively. IMPORTANCEUnderstanding the host pathways hijacked by HCV is critical for developing host-centered anti-HCV approaches. Entry represents a potential target for antiviral strategies; however, no FDA-approved HCV entry inhibitors are currently available. We reported that two host kinases, AAK1 and GAK, regulate HCV assembly. Here, we provide evidence that AAK1 and GAK regulate HCV entry independently of their role in HCV assembly and define the mechanisms underlying AAK1-and GAK-mediated HCV entry. By regulating temporally distinct steps in the HCV life cycle, AAK1 and GAK represent "master regulators" of HCV infection and potential targets for antiviral strategies. Indeed, approved anticancer drugs that potently inhibit AAK1 or GAK inhibit HCV entry in addition to assembly. These results contribute to an understanding of the mechanisms of HCV entry and reveal attractive host targets for antiviral strategies as well as approved candidate inhibitors of these targets, with potential implications for other viruses that hijack clathrin-mediated pathways. H epatitis C virus (HCV) is a major global health problem, estimated to infect 170 million people worldwide (1, 2). HCV persistence results in severe liver disease, including cirrhosis, liver failure, and hepatocellular carcinoma (reviewed in reference...

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Section: Aak1mentioning

confidence: 81%

AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets

Neveu

Ziv-Av

Barouch-Bentov

et al. 2015

J Virol

110

155

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“…Both a and b2 large subunits of AP2 are subdivided into a C-terminal ear domain that binds to clathrin adaptor and accessory proteins and an N-terminal trunk domain that forms the core of AP2 and targets the complex to the plasma membrane [75]. The ear and trunk domains are linked by an unstructured flexible hinge that also provides clathrin-binding sites.…”

Section: Ap2amentioning

confidence: 99%

Caspases rule the intracellular trafficking cartel

2017

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During apoptosis, caspases feast on several hundreds of cellular proteins to orchestrate rapid cellular demise. Indeed, caspases are known to get a taste of every cellular process in one way or another, activating some, but most often shutting them down. Thus, it is not surprising that caspases proteolyze proteins involved in intracellular trafficking with particularly devastating consequences for this important process. This review article focuses on how caspases target the machinery responsible for smuggling goods within and outside the cell.

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“…Most of them consist of an outer "scaffold" layer and an inner "adaptor" layer, although in some cases both layers are tightly intertwined. Among the best-characterized protein coats are those containing clathrin as a scaffold and the AP-1 2 and AP-2 complexes as adaptors (2,3,4,5). AP-1 and AP-2 are heterotetramers composed of homologous ␥-␤1-1-1 and ␣-␤2-2-2 subunits, respectively (Fig.…”

mentioning

confidence: 99%

Bivalent Motif-Ear Interactions Mediate the Association of the Accessory Protein Tepsin with the AP-4 Adaptor Complex

Mattera

Guardia

Sidhu

et al. 2015

Journal of Biological Chemistry

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The heterotetrameric (⑀-␤4-4-4) complex adaptor protein 4 (AP-4) is a component of a non-clathrin coat involved in protein sorting at the trans-Golgi network (TGN). Considerable interest in this complex has arisen from the recent discovery that mutations in each of its four subunits are the cause of a congenital intellectual disability and movement disorder in humans. Despite its physiological importance, the structure and function of this coat remain poorly understood. To investigate the assembly of the AP-4 coat, we dissected the determinants of interaction of AP-4 with its only known accessory protein, the ENTH/VHS-domain-containing protein tepsin. Using a variety of protein interaction assays, we found that tepsin comprises two phylogenetically conserved peptide motifs, Shuttling of cargo between membrane-bound compartments of the endomembrane system of eukaryotic cells is carried out by transport vesicles that bud from a donor compartment and fuse with an acceptor compartment (1). Cargo selection and vesicle budding are both mediated by protein coats that assemble on the cytosolic aspect of the donor compartment from components recruited from the cytosol. To date, about ten different protein coats have been described that participate in vesicular transport at various stages of the endomembrane system. Most of them consist of an outer "scaffold" layer and an inner "adaptor" layer, although in some cases both layers are tightly intertwined. Among the best-characterized protein coats are those containing clathrin as a scaffold and the AP-1 2 and AP-2 complexes as adaptors (2, 3, 4, 5). AP-1 and AP-2 are heterotetramers composed of homologous ␥-␤1-1-1 and ␣-␤2-2-2 subunits, respectively (Fig. 1A). The large ␥ and ␤1 subunits of AP-1, and ␣ and ␤2 subunits of AP-2, have a modular organization consisting of a folded N-terminal "trunk" domain, a largely unstructured "hinge" segment, and a folded C-terminal "ear" or "appendage" domain. The trunk domains of the large subunits, plus the whole and subunits, constitute a "core" that mediates membrane recruitment through interaction with specific phosphoinositides and/or Arf-family GTPases, as well as cargo selection through recognition of sorting signals in the cytosolic tails of transmembrane proteins. The hinge segments extend from the core and interact with the clathrin scaffold via LLDLD-type "clathrin-box" motifs (6). Finally, the ear domains interact with a variety of accessory proteins, some of which regulate coat assembly and interactions with the cytoskeleton, while others function as additional adaptors.X-ray crystallographic analyses of the ␣-and ␤2-ear domains of AP-2 revealed that they have a similar bilobed structure comprising an N-terminal immunoglobulin-like ␤-sandwich subdomain and a C-terminal platform subdomain (7,8,9,10) (Fig. 1A). Accessory proteins interact with the ␣ and ␤2 ear domains via short peptide sequences or structural motifs that bind to sites on either the sandwich or platform subdomains. For instance, DPW (11) and WXX[FW]X[DE] motifs...

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Adaptor protein complexes and intracellular transport

Cited by 146 publications

References 85 publications

AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets

AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets

Caspases rule the intracellular trafficking cartel

Bivalent Motif-Ear Interactions Mediate the Association of the Accessory Protein Tepsin with the AP-4 Adaptor Complex

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