Palmitoylation of SARS‐CoV‐2 S protein is critical for S‐mediated syncytia formation and virus entry

Li, Daoqun; Liu, Yihan; Lu, Yue; Gao, Shan; Zhang, Leiliang

doi:10.1002/jmv.27339

Cited by 37 publications

(45 citation statements)

References 15 publications

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“…This interaction causes the formation of multinucleated syncytia which may contribute to virus propagation and to tissue damage. While syncytia were never observed with SARS-CoV-1, infection with SARS-CoV-2 is reported to induce the formation of multinucleated cells in vitro (153)(154)(155)(156) as well as in vivo (154,(157)(158)(159), leading to the fusion of pneumocytes (157) with the contribution of lymphocytes (159) in the lungs. The propensity of the SARS-CoV-2 spike to induce the formation of multinucleated cells could be related to the processing by cellular proteases, such as furin and TMPRSS2 (156,159), which activates and unleash the fusogenic potential of the viral glycoprotein not only on the viral particle but also on the cell surface.…”

Section: Syncytia Formation By Sars-cov-2 Spike: a Fusogenic Interaction Of Infected And Non-infected Cellsmentioning

confidence: 99%

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

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The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.

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Section: Syncytia Formation By Sars-cov-2 Spike: a Fusogenic Interaction Of Infected And Non-infected Cellsmentioning

confidence: 99%

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

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show abstract

“…DHHC20, -8, and -9 were verified to play certain roles in SARS-CoV-2 spike protein(S) and enveloped protein (Abdulrahman et al, 2021;Mesquita et al, 2021;Puthenveetil et al, 2021). However, conflicting results regarding the palmitoylation sites and palmitoylation enzymes of SARS-CoV-2 spike protein were obtained by different researchers (Mesquita et al, 2021;Puthenveetil et al, 2021;Zeng et al, 2021;Li et al, 2022). Li et al found the cysteines of C-terminal and N-terminal C15 of the spike protein were palmitoylated (Li et al, 2022), while Wu et al reported that N-terminal C15 mutant did not affect the Sacylation of the spike (Wu, Zhang et al, 2021).…”

Section: Palmitoylation Of Viral Proteinsmentioning

confidence: 99%

“…However, conflicting results regarding the palmitoylation sites and palmitoylation enzymes of SARS-CoV-2 spike protein were obtained by different researchers (Mesquita et al, 2021;Puthenveetil et al, 2021;Zeng et al, 2021;Li et al, 2022). Li et al found the cysteines of C-terminal and N-terminal C15 of the spike protein were palmitoylated (Li et al, 2022), while Wu et al reported that N-terminal C15 mutant did not affect the Sacylation of the spike (Wu, Zhang et al, 2021). Using computational, lipidomic, and biochemical approaches, Mesquita et al deciphered the roles of zDHHC20 and zDHHC9 in the palmitoylation of the C terminal cysteines of spike protein in in vivo and in vitro conditions (Mesquita et al, 2021).…”

Section: Palmitoylation Of Viral Proteinsmentioning

confidence: 99%

Protein Palmitoylation Modification During Viral Infection and Detection Methods of Palmitoylated Proteins

Shen

Liu

et al. 2022

Front. Cell. Infect. Microbiol.

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Protein palmitoylation—a lipid modification in which one or more cysteine thiols on a substrate protein are modified to form a thioester with a palmitoyl group—is a significant post-translational biological process. This process regulates the trafficking, subcellular localization, and stability of different proteins in cells. Since palmitoylation participates in various biological processes, it is related to the occurrence and development of multiple diseases. It has been well evidenced that the proteins whose functions are palmitoylation-dependent or directly involved in key proteins’ palmitoylation/depalmitoylation cycle may be a potential source of novel therapeutic drugs for the related diseases. Many researchers have reported palmitoylation of proteins, which are crucial for host-virus interactions during viral infection. Quite a few explorations have focused on figuring out whether targeting the acylation of viral or host proteins might be a strategy to combat viral diseases. All these remarkable achievements in protein palmitoylation have been made to technological advances. This paper gives an overview of protein palmitoylation modification during viral infection and the methods for palmitoylated protein detection. Future challenges and potential developments are proposed.

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“…This suggests that in addition to DHHC9, DHHC15 or DHHC20 can also palmitoylate the spike protein. Others have also shown that DHHC20 is capable of palmitoylating the SARS-CoV-2 spike protein(5,26,60). Among these reports, while Mesquita et al(26) and Li et al(60) also found DHHC9 as a potential spike palmitoylating PAT, Puthenveetil et al did not identify DHHC9 in their screen(5).…”

mentioning

confidence: 99%

“…Others have also shown that DHHC20 is capable of palmitoylating the SARS-CoV-2 spike protein(5,26,60). Among these reports, while Mesquita et al(26) and Li et al(60) also found DHHC9 as a potential spike palmitoylating PAT, Puthenveetil et al did not identify DHHC9 in their screen(5). In this context, it is reasonable to assume that spike protein palmitoylation may be carried out by different DHHC proteins in different cellular compartments during the viral life cycle.…”

mentioning

confidence: 99%

Inhibition of SARS-CoV-2 spike protein palmitoylation reduces virus infectivity

Ramadan

Mayilsamy

McGill

et al. 2021

Preprint

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Spike glycoproteins of almost all enveloped viruses are known to undergo post-translational attachment of palmitic acid moieties. The precise role of such palmitoylation of the spike protein in membrane fusion and infection is not completely understood. Here, we report that palmitoylation of the first five cysteine residues of the c-terminal cysteine-rich domain of the SARS-CoV-2 spike are indispensable for infection, and palmitoylation deficient spike mutants are defective in trimerization and subsequent membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi, and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 spike protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.

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Palmitoylation of SARS‐CoV‐2 S protein is critical for S‐mediated syncytia formation and virus entry

Cited by 37 publications

References 15 publications

SARS-CoV-2 and the Host Cell: A Tale of Interactions

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Protein Palmitoylation Modification During Viral Infection and Detection Methods of Palmitoylated Proteins

Inhibition of SARS-CoV-2 spike protein palmitoylation reduces virus infectivity

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