ESCPE-1 Mediates Retrograde Endosomal Sorting of the SARS-CoV-2 Host Factor Neuropilin-1

Simonetti, Boris; Daly, James L.; Simón‐Gracia, Lorena; Klein, Katja; Weeratunga, Saroja; Antón-Plágaro, Carlos; Tobi, Allan; Hodgson, Lorna; Lewis, Philip A.; Heesom, Kate J; Shoemark, Deborah K.; Davidson, Andrew D.; Collins, Brett M.; Teesalu, Tambet; Yamauchi, Yohei; Cullen, Peter J.

doi:10.1101/2022.01.20.477115

Cited by 4 publications

(15 citation statements)

References 68 publications

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“…To assess the effect on CHC22 distribution when SNX5 levels were altered, a HeLa cell line engineered by CRISPR to delete the genes encoding SNX5 and SNX6 (ΔSNX5/6) , was used (Figure 1C). This SNX5/6-null cell line was previously produced for, and characterized in, studies of Retromer and ESCPE-1 trafficking (Simonetti et al, 2022; Simonetti et al, 2017; Simonetti et al, 2019). In those studies, phenotypes were only observed when both SNX5 and SNX6 were deleted, indicating their functional redundancy.…”

Section: Resultsmentioning

confidence: 99%

“…The requirement of SNX5/6 for CHC22 localization raises the question of whether known partners of SNX5/6 are also involved. To address this, CHC22 localization was tested in HeLa cells lacking SNX1/2, which dimerize with SNX5/6 in the endosomal ESCPE-1 complex (Simonetti et al, 2022; Simonetti et al, 2017; Simonetti et al, 2019), with further examination of whether CHC22 localization is affected in cells lacking the human VPS26A/B:VPS35:VPS29 Retromer complex. The retromer-null ( ΔVPS35 ) and SNX1/2-null cells ( ΔSNX1/2 ) were produced by CRISPR engineering and characterized in earlier studies (Simonetti et al, 2022; Simonetti et al, 2017; Simonetti et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…These SNX-BAR protein family members were initially implicated in Retromer sorting at endosomes by homology with yeast proteins (Rojas et al, 2007; Simonetti and Cullen, 2018; van Weering et al, 2012; Wassmer et al, 2007). However, it is now established that SNX5/6 heterodimerize with SNX1, or its functionally-redundant paralogue protein SNX2, to form the ESCPE-1 complex, which is distinct from conventional Retromer and mediates separate endosomal sorting pathways (Evans et al, 2020; Simonetti et al, 2022; Simonetti et al, 2019). The resulting SNX-BAR ESCPE-1 heterodimers interact with lipids through the PX domain of SNX1/2 and with cargo through the PX of SNX5/6 (Evans et al, 2020; Kvainickas et al, 2017; Simonetti et al, 2017; van Weering et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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CHC22 clathrin functions in the early secretory pathway by two-site interaction with SNX5 and p115

Greig

Bates

Yin

et al. 2022

Preprint

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The two clathrin isoforms, CHC17 and CHC22, generate separate vesicles for intracellular transport. CHC17 mediates endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, transports the glucose transporter GLUT4 from the endoplasmic-reticulum-to-Golgi intermediate compartment (ERGIC) to an intracellular GLUT4 storage compartment (GSC) from where GLUT4 is mobilized by insulin. Molecular determinants distinguishing the trafficking of CHC22 clathrin from CHC17 within the GLUT4 pathway are defined in this study. The C-terminal trimerization domain of CHC22, but not CHC17, directly binds SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. Both the SNX5-BAR domain and an isoform-specific patch on the CHC22 N-terminal domain separately mediate binding to p115, and both interactions are required for CHC22 recruitment. These indirect and direct interactions at each CHC22 terminus are required for GLUT4 traffic to the GSC, defining a dual mechanism regulating the function of CHC22 in glucose metabolism.Summary statementCHC22 clathrin uses a bipartite mechanism for recruitment to the early secretory pathway, where it targets the GLUT4 transporter to an insulin-responsive intracellular compartment. Localization requires binding to the ERGIC tether p115 through sorting nexin 5 interaction at the CHC22 C-terminus and directly via the CHC22 N-terminal domain.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CHC22 clathrin functions in the early secretory pathway by two-site interaction with SNX5 and p115

Greig

Bates

Yin

et al. 2022

Preprint

Self Cite

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“…14,46 However, they have also been shown to coordinate the process of membrane remodelling and cargo sorting in a Retromer-independent fashion and the complex has been named the "Endosomal SNX-BAR Sorting Complex for Promoting Exit," or ESCPE-1 42,47,48 (Figure 1B). ESCPE-1 heterodimers are best characterized for their function in the tubular-based recycling of several transmembrane proteins from endosomes to the TGN (e.g., CI-MPR), or to the plasma membrane (e.g., insulin-like growth factor 1 receptor, IGF1R) 24,42,43,[47][48][49][50][51] (Figure 1A-C). This role was identified through the depletion of ESCPE-1 subunits, which triggers a marked localisation of CI-MPR and IGF1R in endosomes, while failing to repopulate the TGN and the cell surface respectively.…”

Section: Molecular Assembly and Function Of Escpe-1mentioning

confidence: 99%

Out of the ESCPE room: Emerging roles of endosomal SNX‐BARs in receptor transport and host–pathogen interaction

Simonetti

Daly

Cullen

2023

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Several functions of the human cell, such as sensing nutrients, cell movement and interaction with the surrounding environment, depend on a myriad of transmembrane proteins and their associated proteins and lipids (collectively termed “cargoes”). To successfully perform their tasks, cargo must be sorted and delivered to the right place, at the right time, and in the right amount. To achieve this, eukaryotic cells have evolved a highly organized sorting platform, the endosomal network. Here, a variety of specialized multiprotein complexes sort cargo into itineraries leading to either their degradation or their recycling to various organelles for further rounds of reuse. A key sorting complex is the Endosomal SNX‐BAR Sorting Complex for Promoting Exit (ESCPE‐1) that promotes the recycling of an array of cargos to the plasma membrane and/or the trans‐Golgi network. ESCPE‐1 recognizes a hydrophobic‐based sorting motif in numerous cargoes and orchestrates their packaging into tubular carriers that pinch off from the endosome and travel to the target organelle. A wide range of pathogens mimic this sorting motif to hijack ESCPE‐1 transport to promote their invasion and survival within infected cells. In other instances, ESCPE‐1 exerts restrictive functions against pathogens by limiting their replication and infection. In this review, we discuss ESCPE‐1 assembly and functions, with a particular focus on recent advances in the understanding of its role in membrane trafficking, cellular homeostasis and host–pathogen interaction.

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“…Endosomal sorting of NRP1 to the trans-golgi network (TGN) occurs via its direct interaction with ESCPE-1 (endosomal SNX-BAR sorting complex promoting exit 1), which is an endosomal coat complex important for retrograde trafficking of transmembrane proteins. ESCPE-1 consists of a heterodimer of functionally redundant sorting nexin 1 (SNX1) or SNX2, with SNX5 or SNX6 (Simonetti et al, 2022). In turn, ESCPE-1 was shown to interact with SARS-CoV-2 S and mediate the trafficking of S-coated nanoparticles to the TGN.…”

Section: Endosomal Trafficking and Sars-cov-2 Entrymentioning

confidence: 99%

A snapshot of protein trafficking in SARS‐CoV‐2 infection

Bartenschlager

2022

Biology of the Cell

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SARS‐CoV‐2 is a human pathogenic virus responsible for the COVID‐19 (coronavirus disease 2019) pandemic. The infection cycle of SARS‐CoV‐2 involves several related steps, including virus entry, gene expression, RNA replication, assembly of infectious virions and their egress. For all of these steps, the virus relies on and exploits host cell factors, cellular organelles, and processes such as endocytosis, nuclear transport, protein secretion, metabolite transport at membrane contact sites (MSC) and exocytotic pathways. To do this, SARS‐CoV‐2 has evolved multifunctional viral proteins that hijack cellular factors and modulate their function by unique strategies. In this Review, we highlight cellular trafficking factors, processes, and organelles of relevance to the SARS‐CoV‐2 infection cycle and how viral proteins make use of and perturb cellular transport during the viral infection cycle.

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ESCPE-1 Mediates Retrograde Endosomal Sorting of the SARS-CoV-2 Host Factor Neuropilin-1

Cited by 4 publications

References 68 publications

CHC22 clathrin functions in the early secretory pathway by two-site interaction with SNX5 and p115

CHC22 clathrin functions in the early secretory pathway by two-site interaction with SNX5 and p115

Out of the ESCPE room: Emerging roles of endosomal SNX‐BARs in receptor transport and host–pathogen interaction

A snapshot of protein trafficking in SARS‐CoV‐2 infection

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