EARP is a multisubunit tethering complex involved in endocytic recycling

Schindler, Christina; Chen, Yu; Pu, Jing; Guo, Xiaoli; Bonifacino, Juan S.

doi:10.1038/ncb3129

Cited by 117 publications

(169 citation statements)

References 64 publications

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“…In contrast, depletion of protein components of the Retromer complex (45) inhibited VACV spread to a lesser extent, suggesting that a specific set of transport factors are needed. Recently, the EARP complex was described, in which the VPS54 component of GARP is replaced by the coil-coil domain-containing 132 protein (CCDC132, also called syndetin) (26). Functionally, EARP is required for endosome recycling back to the membrane, while GARP is needed for endosome-to-Golgi trafficking.…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial (Shiga and cholera) and plant (ricin and abrin) toxins (20) as well as some nonenveloped viruses, including simian virus 40 (SV40), polyomavirus, adeno-associated virus, and papillomavirus (21)(22)(23)(24), exploit the retrograde path to enter cells. Retrograde transport is highly selective and depends on numerous tethering factors, small GTPases, and SNARES (25,26). The small molecule Retro-2 interferes with retrograde transport from early endosome to the TGN specifically and protects against ricin and Shiga-like toxins (27) and virus entry (22)(23)(24), while having little or no apparent cellular toxicity.…”

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confidence: 99%

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Retrograde Transport from Early Endosomes to the trans -Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions

Sivan

Weisberg

Americo

et al. 2016

J Virol

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The anterograde pathway, from the endoplasmic reticulum through the trans-Golgi network to the cell surface, is utilized by trans-membrane and secretory proteins. The retrograde pathway, which directs traffic in the opposite direction, is used following endocytosis of exogenous molecules and recycling of membrane proteins. Microbes exploit both routes: viruses typically use the anterograde pathway for envelope formation prior to exiting the cell, whereas ricin and Shiga-like toxins and some nonenveloped viruses use the retrograde pathway for cell entry. Mining a human genome-wide RNA interference (RNAi) screen revealed a need for multiple retrograde pathway components for cell-to-cell spread of vaccinia virus. We confirmed and extended these results while discovering that retrograde trafficking was required for virus egress rather than entry. Retro-2, a specific retrograde trafficking inhibitor of protein toxins, potently prevented spread of vaccinia virus as well as monkeypox virus, a human pathogen. Electron and confocal microscopy studies revealed that Retro-2 prevented wrapping of virions with an additional double-membrane envelope that enables microtubular transport, exocytosis, and actin polymerization. The viral B5 and F13 protein components of this membrane, which are required for wrapping, normally colocalize in the trans-Golgi network. However, only B5 traffics through the secretory pathway, suggesting that F13 uses another route to the trans-Golgi network. The retrograde route was demonstrated by finding that F13 was largely confined to early endosomes and failed to colocalize with B5 in the presence of Retro-2. Thus, vaccinia virus makes novel use of the retrograde transport system for formation of the viral wrapping membrane. IMPORTANCEEfficient cell-to-cell spread of vaccinia virus and other orthopoxviruses depends on the wrapping of infectious particles with a double membrane that enables microtubular transport, exocytosis, and actin polymerization. Interference with wrapping or subsequent steps results in severe attenuation of the virus. Some previous studies had suggested that the wrapping membrane arises from the trans-Golgi network, whereas others suggested an origin from early endosomes. Some nonenveloped viruses use retrograde trafficking for entry into the cell. In contrast, we provided evidence that retrograde transport from early endosomes to the trans-Golgi network is required for the membrane-wrapping step in morphogenesis of vaccinia virus and egress from the cell. The potent in vitro inhibition of this step by the drug Retro-2 suggests that derivatives with enhanced pharmacological properties might serve as useful antipoxviral agents. V accinia virus (VACV) is the prototype member of the poxvirus family of cytoplasmic double-stranded DNA viruses (1). The first infectious form of VACV, the intracellular mature virion (MV), is a brick-shaped particle consisting of a nucleoprotein core, lateral bodies, and a surrounding lipoprotein membrane (2). A subset of cytoplasmic MVs are wr...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Retrograde Transport from Early Endosomes to the trans -Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions

Sivan

Weisberg

Americo

et al. 2016

J Virol

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“…5) where TGFBRAP1 in CORVET would have to release VPS11, thereby allowing VPS11 to bind VPS39 and recruit the entire HOPS complex to RAB7-RILP during RAB5 (EEs) to RAB7 (LE) conversion. Specific targeting of tethering complexes by modulation of targeting subunits was recently also shown for GARP and EARP tethering on Golgi and EEs, respectively, indicating this might be a common mechanism in the regulation of vesicular fusion (43). TGFBRAP1 to VPS39 exchange might further be regulated by proteins such as MON1-CCZ1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Kant

Jonker

Wijdeven

et al. 2015

Journal of Biological Chemistry

117

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Background:The CORVET and HOPS complexes regulate endosomal cargo trafficking but have not been well characterized in mammals. Results: A detailed analysis of subunit interactions within the mammalian CORVET, HOPS, and VIPAS39/VPS33B complexes. Conclusion: Tethering complexes have adapted to the higher complexity of trafficking in mammalian cells. Significance: This work provides a detailed architectural insight into the mammalian endosomal tethering complexes.

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“…Schindler et al (2015) recently showed that several components of this complex, including VPS52, also take part in a complex involved in endosome to plasma membrane trafficking, pointing to different functions of GARP-complex proteins in cellular trafficking. Although the role of VPS52 in plant cellular trafficking is not well understood, this protein was previously shown to localize to post-Golgi and prevacuolar compartments, suggesting it may have similar functions in trafficking as in other systems (Lobstein et al, 2004;Guermonprez et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

An Aphid Effector Targets Trafficking Protein VPS52 in a Host-Specific Manner to Promote Virulence

2017

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Plant-and animal-feeding insects secrete saliva inside their hosts, containing effectors, which may promote nutrient release and suppress immunity. Although for plant pathogenic microbes it is well established that effectors target host proteins to modulate host cell processes and promote disease, the host cell targets of herbivorous insects remain elusive. Here, we show that the existing plant pathogenic microbe effector paradigm can be extended to herbivorous insects in that effector-target interactions inside host cells modify critical host processes to promote plant susceptibility. We showed that the effector Mp1 from Myzus persicae associates with the host Vacuolar Protein Sorting Associated Protein52 (VPS52). Using natural variants, we provide a strong link between effector virulence activity and association with VPS52, and show that the association is highly specific to M. persicae-host interactions. Also, coexpression of Mp1, but not Mp1-like variants, specifically with host VPS52s resulted in effector relocalization to vesicle-like structures that associate with prevacuolar compartments. We show that high VPS52 levels negatively impact virulence, and that aphids are able to reduce VPS52 levels during infestation, indicating that VPS52 is an important virulence target. Our work is an important step forward in understanding, at the molecular level, how a major agricultural pest promotes susceptibility during infestation of crop plants. We give evidence that an herbivorous insect employs effectors that interact with host proteins as part of an effective virulence strategy, and that these effectors likely function in a species-specific manner.

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EARP is a multisubunit tethering complex involved in endocytic recycling

Cited by 117 publications

References 64 publications

Retrograde Transport from Early Endosomes to the trans -Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions

Retrograde Transport from Early Endosomes to the trans -Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

An Aphid Effector Targets Trafficking Protein VPS52 in a Host-Specific Manner to Promote Virulence

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