Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

To, Janet; Torres, Jaume

doi:10.1007/978-981-10-8456-0_15

Cited by 10 publications

(11 citation statements)

References 290 publications

(314 reference statements)

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“…Evidence suggests that CoV E proteins interact with host cell proteins to influence pathogenicity ( 31 ). Interaction of SARS-CoV E with the PDZ (postsynaptic density protein 95/discs Large/zonula occludens 1) domain-containing scaffolding protein syntenin and with the tight junction protein PALS1 (protein associated with Lin Seven 1) through its PBM (PDZ-binding motif) domain implicates the E protein as a pathogenic determinant ( 32 – 34 ).…”

Section: Discussionmentioning

confidence: 99%

The Infectious Bronchitis Coronavirus Envelope Protein Alters Golgi pH To Protect the Spike Protein and Promote the Release of Infectious Virus

Westerbeck

Machamer

2019

J Virol

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Coronaviruses (CoVs) assemble by budding into the lumen of the early Golgi complex prior to exocytosis. The small CoV envelope (E) protein plays roles in assembly, virion release, and pathogenesis. CoV E has a single hydrophobic domain (HD), is targeted to Golgi membranes, and has cation channel activity in vitro. The E protein from avian infectious bronchitis virus (IBV) has dramatic effects on the secretory system, which require residues in the HD. Mutation of the HD of IBV E in a recombinant virus background results in impaired growth kinetics, impaired release of infectious virions, accumulation of IBV spike (S) protein on the plasma membrane compared to wild-type (WT) IBV-infected cells, and aberrant cleavage of IBV S on virions. We previously reported the formation of two distinct oligomeric pools of IBV E in transfected and infected cells. Disruption of the secretory pathway by IBV E correlates with a form that is likely monomeric, suggesting that the effects on the secretory pathway are independent of E ion channel activity. Here, we present evidence suggesting that the monomeric form of IBV E correlates with an increased Golgi luminal pH. Infection with IBV or expression of IBV E induces neutralization of Golgi pH, promoting a model in which IBV E alters the secretory pathway through interaction with host cell factors, protecting IBV S from premature cleavage and leading to the efficient release of infectious virus from the cells. This is the first demonstration of a coronavirus-induced alteration in the microenvironment of the secretory pathway. IMPORTANCE Coronaviruses are important human pathogens with significant zoonotic potential. Progress has been made toward identifying potential vaccine candidates for highly pathogenic human CoVs, including the use of attenuated viruses that lack the CoV E protein or express E mutants. However, no approved vaccines or antiviral therapeutics exist. Understanding the role of the CoV E protein in virus assembly and release is thus an important prerequisite for potential vaccines as well as in identifying novel antiviral therapeutics.

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Section: Discussionmentioning

confidence: 99%

The Infectious Bronchitis Coronavirus Envelope Protein Alters Golgi pH To Protect the Spike Protein and Promote the Release of Infectious Virus

Westerbeck

Machamer

2019

J Virol

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“…Influenza viroporins are also involved in viral pathogenesis by engaging in critical interactions with viral proteins or disrupting normal host cellular pathways through coordinated interactions with host proteins. The reader is referred to a recent review on this subject [148] that provides an update on the characterization of the main PPIs for most viroporins, as well as the role of viroporins in these PPI interactions. In the next part of this review, we highlight and summarize the nature and outcome of some of these protein–protein interactions involving M2, and how the influenza virus may exploit these host cell factors to its advantage.…”

Section: Protein–protein Interactions (Ppis)mentioning

confidence: 99%

Viroporins in the Influenza Virus

Torres

2019

Cells

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Influenza is a highly contagious virus that causes seasonal epidemics and unpredictable pandemics. Four influenza virus types have been identified to date: A, B, C, and D, where only A–C are known to infect humans. Influenza A (IAV) and B (IBV) viruses are responsible for seasonal influenza epidemics in humans and are responsible for up to a billion flu infections annually. The M2 protein is present in all influenza types and belongs to the class of viroporins (i.e., small proteins that form ion channels that increase membrane permeability in virus-infected cells). In influenza A and B, AM2 and BM2 are predominantly proton channels, although they also show some permeability to monovalent cations. In contrast, M2 proteins in influenza C (ICV) and D (IDV), CM2 and DM2, appear to be especially selective for chloride ions, with possibly some permeability to protons. These differences point to different biological roles for M2 in types A and B versus C and D, which is also reflected in their sequences. AM2 is by far the best characterized viroporin, and mechanistic details and rationale of its acid activation, proton selectivity, unidirectionality and relative low conductance are just beginning to be understood. The present review summarizes the biochemical and structural aspects of influenza viroporins and discusses the most relevant aspects of function, inhibition and interaction with the host.

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“…proteins, both by themselves and in various combinations with host proteins, and comparing homologous proteins from SARS-CoV-1 and SARS-CoV-2. Plasma membrane viroporins are important for many viruses (1)(2)(3)(4)(5), and we tested for their presence in SARS-CoV-2 by expressing SARS-CoV-1 and SARS-CoV-2 proteins in Xenopus oocytes.…”

Section: Introductionmentioning

confidence: 99%

“…It is important to understand how the various proteins encoded by SARS-CoV-2 interact with endogenous human proteins (2,6,7). SARS-CoV-2 must interact with host proteins to replicate (8).…”

Section: Introductionmentioning

confidence: 99%

Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins

Grant

Lester

2021

Biophysical Journal

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), encodes several proteins whose roles are poorly understood. We tested their ability either to directly form plasma membrane ion channels or to change functions of two mammalian plasma membrane ion channels, the epithelial sodium channel (ENaC) and the α3β4 nicotinic acetylcholine receptor (nAChR). In mRNA-injected Xenopus oocytes, none of nine SARS-CoV-2 proteins or two SARS-CoV-1 proteins produced conductances, nor did co-injection of several combinations. Immunoblots for ORF8, spike (S), and envelope (E) proteins revealed that the proteins are expressed at appropriate molecular weights. In experiments on co-expression with ENaC, three tested SARs proteins (SARS-CoV-1 E, SARS-CoV-2 E, and SARS-CoV-2 S) markedly decrease ENaC currents. SARS-CoV-1 S protein decreases ENaC currents modestly. Co-expressing the E proteins, but not the S proteins, with α3β4 nAChRs significantly reduces acetylcholine-induced currents. ENaC inhibition does not occur if the SARS-CoV protein mRNAs are injected 24 h after the ENaC mRNAs, suggesting that SARS-CoV proteins affect early step(s) in functional expression of channel proteins. Consistent with the hypothesis that the SARS-CoV-2 S protein-induced ENaC inhibition involves competition for available protease, mutating the furin cleavage site in SARS-CoV-2 S protein partially relieves inhibition of ENaC currents. Extending previous suggestions that SARS proteins affect ENaC currents via protein kinase C (PKC) activation, PKC activation via phorbol 12-myristate 13-acetate (PMA) decreases ENaC and α3β4 activity. PMA application reduced membrane capacitance ∼ 5%, presumably via increased endocytosis; but this decrease is much smaller than the SARS proteins’ effects on conductances. Also, incubating oocytes in Gö-6976, a PKCα and PKCβ inhibitor, did not alter E or S protein-induced channel inhibition. We conclude that SARS-CoV-1 and SARS-CoV-2 proteins alter the function of human plasma membrane channels, via incompletely understood mechanisms. These interactions may play a role in COVID-19 pathophysiology.

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Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

Cited by 10 publications

References 290 publications

The Infectious Bronchitis Coronavirus Envelope Protein Alters Golgi pH To Protect the Spike Protein and Promote the Release of Infectious Virus

The Infectious Bronchitis Coronavirus Envelope Protein Alters Golgi pH To Protect the Spike Protein and Promote the Release of Infectious Virus

Viroporins in the Influenza Virus

Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins

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