Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Pasquale, Valeria De; Quiccione, Miriam Shasa; Tafuri, Simona; Avallone, Luigi; Pavone, Luigi Michele

doi:10.3390/ijms22126574

Cited by 55 publications

(44 citation statements)

References 231 publications

(453 reference statements)

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“…DX600 is a competitive peptide inhibitor of ACE2 that only modestly inhibits the cellular entry of SARS-CoV-2 (and -1), suggesting that ACE2’s enzymatic activity is not essential for viral endocytosis [ 25 , 32 , 33 ]. On the other hand, heparin reduces SARS-CoV-1 and -2 infection very efficiently by directly competing with viral binding to host HSPGs [ 22 , 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread.

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Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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“…These macromolecules control several regulatory mechanisms related to the formation of extracellular gradients, cellular growth and proliferation, cell adhesion, migration and invasion, membrane trafficking and angiogenesis (4,5). By interfering with these cellular events, HSPGs display important functions both in physiology and pathology, controlling embryonic development, ECM assembly and maintenance, tissue remodelling, metabolism homeostasis, pathogen invasion and inflammation (6)(7)(8)(9)(10)(11)(12). Particularly in cancer, HSPGs and HS chains hold very relevant roles in the development and progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients’ stratification and cancer treatment.

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“…Influenza viruses bind to variants of sialic acid both during entry into and egress from their host cells, and utilize the activity of viral neuraminidase to promote the release of newly synthesized virions from cell surface glycans (McAuley et al, 2019). Enzymatic release of SARS-CoV-2 from host cell HS GAGs has not been demonstrated, but has been described for instance in the case of Herpes simplex virus 1, which is released from the cell surface by heparanase degradation of HS GAGs attached to syndecan-1 (de Pasquale et al, 2021;Hadigal et al, 2020). As discussed below, CoV infection causes disassembly of the Golgi apparatus (Cortese et al, 2020;Hackstadt et al, 2021;Lavi et al, 1996;Ruch & Machamer, 2012;Ulasli et al, 2010), where HS synthesis normally takes place (Prydz & Dalen, 2000).…”

Section: Virus Entry and Eg Re Ss: G Lyc An B Ind Ing At The Ri G Ht ...mentioning

confidence: 99%

The life cycle and enigmatic egress of coronaviruses

Prydz

Saraste²

2022

Molecular Microbiology

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There has been considerable recent interest in the life cycle of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of the Covid-19 pandemic. Practically every step in CoV replication-from cell attachment and uptake via genome replication and expression to virion assembly has been considered as a specific event that potentially could be targeted by existing or novel drugs.Interference with cellular egress of progeny viruses could also be adopted as a possible therapeutic strategy; however, the situation is complicated by the fact that there is no broad consensus on how CoVs find their way out of their host cells. The viral nucleocapsid, consisting of the genomic RNA complexed with nucleocapsid proteins obtains a membrane envelope during virus budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)-Golgi interface. From here, several alternative routes for CoV extracellular release have been proposed. Strikingly, recent studies have shown that CoV infection leads to the disassembly of the Golgi ribbon and the mobilization of host cell compartments and protein machineries that are known to promote Golgi-independent trafficking to the cell surface. Here, we discuss the life cycle of CoVs with a special focus on different possible pathways for virus egress.

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Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Cited by 55 publications

References 231 publications

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

The life cycle and enigmatic egress of coronaviruses

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