Koronaviruksen viroporiini vaikuttaa NOD - järjestelmän puolella

 Koronaviruksen   E ( envelope) proteiinista  poiminstoja  artikkelista 2019;

https://www.frontiersin.org/articles/10.3389/fmicb.2019.00050/full

Vuodetla  2019 uusinta  CoV E- proteiinista.

• ( Alustavaa perustietoa  vuodelta 2003 Perustaa vuodelta 2003:  https://www.sciencedirect.com/science/article/pii/S1672022903010179?via%3Dihub#bib23Tässä pidettiin E-proteiinia  viruksen proteiniien  suurimpana mysteerinä )

Vuodelta 2019 artikkeli  :https://www.ncbi.nlm.nih.gov/pubmed/31133031
SITAATTI:

 Abstract BACKGROUND:

Coronaviruses (CoVs) primarily cause enzootic infections in birds and mammals but, in the last few decades, have shown to be capable of infecting humans as well. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and, more recently, Middle-East respiratory syndrome (MERS) has demonstrated the lethality of CoVs when they cross the species barrier and infect humans. A renewed interest in coronaviral research has led to the discovery of several novel human CoVs and since then much progress has been made in understanding the CoV life cycle. The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis. Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins. MAIN BODY:
This review aims to establish the current knowledge on CoV E by highlighting the recent progress that has been made and comparing it to previous knowledge. It also compares E to other viral proteins of a similar nature to speculate the relevance of these new findings. Good progress has been made but much still remains unknown and this review has identified some gaps in the current knowledge and made suggestions for consideration in future research. CONCLUSIONS:
The most progress has been made on SARS-CoV E, highlighting specific structural requirements for its functions in the CoV life cycle as well as mechanisms behind its pathogenesis. Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates. The high mortality rate of certain CoVs, along with their ease of transmission, underpins the need for more research into CoV molecular biology which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.KEYWORDS:

Assembly; Budding; Coronavirus; Envelope protein; Topology; Viroporin

PMID:

31133031

PMCID:

PMC6537279

DOI:

10.1186/s12985-019-1182-0

[Indexed for MEDLINE]

Free PMC Article
(29.2. 2020  Poimintoja, sitaatteja artikkelista  CoV E-proteiini keskiössä:)

• Together, M and E make up the viral envelope and their interaction is sufficient for the production and release of VLPs [37, 60,61,62,63,64].
•  The E protein is the smallest of the major structural proteins, but also the most enigmatic. During the replication cycle, E is abundantly expressed inside the infected cell, but only a small portion is incorporated into the virion envelope [65]. 
•  The majority of the protein is localised at the site of intracellular trafficking, viz. the ER, Golgi, and ERGIC, where it participates in CoV assembly and budding [66]. 
•  Recombinant CoVs have lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation [35, 39, 40, 67, 68].
•  Coronaviruses are distinct from other well-studied enveloped viruses in that they bud into the ERGIC, from where they acquire their membrane envelope [89]. Once in the lumen of the ERGIC, infectious virions make their way through the host secretory pathway to, ultimately, be released from the infected cell [90]. Accordingly, the E protein is localized mainly to the ER and Golgi-complex where it participates in the assembly, budding, and intracellular trafficking of infectious virions [56, 66, 71, 91].
•  The rationale for the multiple membrane topologies has been suggested in that, between the different CoV species, the E protein might not exhibit a uniform membrane topology or that the orientation of E varies depending on the level of protein expression or oligomerization [69]. Alternatively, the function of the E protein might dictate its membrane topology, depending on whether it is required to function as an ion channel or its involvement in the viral envelope during assembly [41].
•  Of the CoV E proteins, only IBV, SARS-CoV, and MHV have been found to be palmitoylated [73, 93, 117]. A number of integral membrane proteins are substrates for palmitoylation where the cysteine residues adjacent to the TMDs serve as the targets [118, 119].  palmitoylation of E plays an essential part in the viral assembly of MHV [117]. palmitoylation alone of the SARS-CoV E protein does not affect its localization. Rather, it is possible that a loss of both the Golgi-targeting information in the TMD and the palmitoylated cysteine residues leads to the loss of localization as well as membrane its association [65]. 
•  Coronavirus E proteins, along with other members of the Nidovirales order, reportedly have no myristoylation motif and it is suggested to be a feature unique only to the Arteriviridae family in the order of Nidovirales [80]. However, there appears to be no experimental evidence to support this.
•  Ubiquitination and its counterpart, deubiquitination, are well-characterised post-translational modifications with that serve to maintain homeostasis through the regulation of cellular protein levels and their functions [128]. Viruses can exploit this component of the host cell machinery, or even encode their own ubiquitinating/deubiquitinating enzymes to drive the viral life cycle [129]. 
•   Only SARS-CoV E has so far been reported to be ubiquitinated, although the relevance has not yet been determined. 
• The SARS-CoV non-structural protein (nsp) 3 co-localises with E and its interaction was mediated through the N-terminal ubiquitin-like domain-1 of nsp3. Independently, a ubiquitination assay further demonstrated that E can be ubiquitinated and that its ubiquitination status inversely correlates to its stability and half-life [128, 130]
•  Moreover, given the late expression of SARS-CoV accessory protein 8b, Keng, Åkerström [130] suggested that it might function to modulate viral production by down-regulating E production and in doing so maintain an optimal viral titre. However, this will need to be confirmed in the context of a natural infection.
•   Very little information is available on the glycosylation of CoV E and its role
•  , residue N66 was shown to be glycosylated and, more interestingly, mutation of this residue generated higher molecular weight forms resembling dimers and trimers of the E protein. This suggests that glycosylation of N66 might function to prevent oligomerization of the E protein, possibly to promote a specific role of the E protein. Accordingly, multimeric forms of the E protein may not be glycosylated on N66 possibly to promote the functioning of E in other capacities [134].
• Clearly, more research is needed to determine whether all CoV E proteins are glycosylated, or whether it is unique to SARS-CoV that might confer to it certain pathogenic features, and what the importance of E protein glycosylation is.
•  The CoV E protein is unique in that it can form homotypic interactions, which allows it to oligomerise and generate an ion-channel protein known as a viroporin [135, 136].
•  The ability of CoV E to assemble into homopentameric structures is clearly important in the formation of a functional CoV E viroporin [75, 76, 135,136,137,138, 140].
• Experimental data on a physical interaction between CoV S and E is extremely limited with the exception of one study, which showed that SARS-CoV S is an interacting partner of E [128].  
• To date, E has only been reported to interact with five host proteins, i.e. Bcl-xL, PALS1, syntenin, sodium/potassium (Na⁺/K⁺) ATPase α-1 subunit, and stomatin [18, 66, 82, 87]. 
•   Yang, Xiong [87] proposed that the interaction between E and Bcl-xL contributed to the SARS-CoV-induced lymphopenia observed in most SARS patients. Teoh, Siu [82] reported that the E–PALS1 interaction disrupts tight junctions in the lungs, suggesting a mechanism whereby SARS-CoV virions can breach the alveolar wall and develop into a systemic infection. 
•   it is of therapeutic importance that more E interaction partners be identified as inhibitors of p38 mitogen-activated protein kinase (MAPK) were shown to increase the survival rate of mice, protecting them from a lethal infection [18, 158].
•  Coronavirus-infected cells contain several different membranous structures, including double-membrane vesicles (DMVs) and convoluted membranes (CMs) [172,173,174,175]. However, little is known about exactly how these structures are formed and which viral and/or host proteins are involved in this process.
•  Model proposed by Hagemeijer, Monastyrska [177] for the induction of ER membrane curvature. The luminal loops of CoV nsp3 and 4 are required to initiate rearrangement of the ER membrane and produce the DMVs characteristically seen in CoV-infected cells
•  This underpins the importance of establishing a unanimous topology for the E protein as this model could be applied to the induction of membrane curvature by E, provided E can assume multiple topologies during an infection. Should it be demonstrated that E can take on a topology with a luminal loop, this would not be inconceivable as a possible mechanism for the induction of membrane curvature initiated by E or in which E participates. 
•  s heterotypic interactions of nsp3 and 4 are required to induce ER membrane curvature, and the expression of both M and E is required for the formation of smooth, spherical CoV VLPs, 
•  The role of E has also been proposed to be merely catalytic by functioning to pinch off, or in the scission of, the viral particle from the ER membrane during the terminal phase of budding [63].
• Broadly, enveloped viruses can accomplish membrane scission either by hijacking/exploiting the host cell’s scission machinery or through the expression of their own scission proteins [179].
•   it is nearly impossible to say whether E mediates scission in an ESCRT-dependent manner or not ( My Comment: Really possible!)
• . Synthetic peptides corresponding to the full-length SARS-CoV E viroporin have also recently been shown to be capable of transporting Ca²⁺ and was linked to the inflammatory response often observed in ARDS [221]. This is the only study so far to have shown that the E viroporin of any CoV is capable of Ca²⁺ transport.
•  CoV E has an anti-apoptotic function in infected cells by suppressing the UPR during infection, likely as a survival mechanism and to continue viral propagation.
•  --demonstrating an association between E viroporin activity and inflammation. Recently, the transport of Ca²⁺ by SARS-CoV E was shown to trigger inflammasome activation [221]. This establishes the link between inflammasome induction by SARS-CoV E and the inflammatory-mediated lung damage seen in SARS-CoV-infected mice [77].
• The authors concluded that this ion-channelling function confers a selective advantage to the virus [77]. The reduction of inflammatory cytokines in the absence of CoV E ion channel activity suggests that inhibition of the CoV E viroporin limits CoV pathogenicity and could be of therapeutic value to CoV infections.
•  . A few studies have investigated the potential of rCoVs with a mutated E or lacking E, specifically focussing on SARS- and MERS-CoV, as live attenuated vaccine candidates with some promising results [34, 36, 165, 249, 250]. 
• Vaccinated animal models developed robust immune responses, both cellular and humoral, and were protected against infective challenges. This shows that CoV vaccines with mutated or deficient in E can potentially be used for prophylactic treatment, but the duration of immunity does not seem to have been established yet.
•  Autophagy is a cellular process that recycles excess or damaged cellular material to maintain the energy levels of the cell and ensure its survival. The material is removed from the cytoplasm by forming enclosed DMVs known as autophagosomes and then fused with lysosomes to be degraded [268, 269]. Recent studies have increasingly pointed to the involvement of autophagy components in viral infections [270]. Some suggest that it might have an antiviral function by inhibiting viral replication [271,272,273]. Others reported inhibition or subversion of autophagy as a defence mechanism to promote viral propagation [274,275,276]. Others still, notably RNA viruses, appear to exploit autophagy for the purpose of viral propagation [277, 278]. 
• These studies suggest the possibility of CoVs exploiting autophagy for replicative purposes. It has even been proposed that the DMVs formed in CoV-infected cells might be the result of autophagy and derived from the rough ER [281].  
• Considering these studies, along with the ability of SARS-CoV to channel Ca²⁺, it is not inconceivable that CoV E viroporin could induce autophagy in CoV-infected cells by increasing cytosolic Ca²⁺. However, experimental evidence would be required to support the possibility of such a mechanism in CoVs.
•   Deletion of E from SARS-CoV attenuates the virus whereas, in the case of MERS-CoV, virions are propagation deficient [35, 165].
•   Certain CoV accessory proteins appear to be able to complement, or sometimes even compensate for, the absence of E in processes such as assembly, release, and the pathogenesis of some CoVs [30].
•   It is particularly noteworthy that SARS-CoV encodes two accessory proteins, 3a and 8a, that might exhibit relative compensatory functions in the absence of E [285, 286]
•  What is clear, though, is that viroporin proteins, case in point IAV M2, can exhibit a multitude of different functions independent of their ion-channel properties [153, 184].
•  Although a lot of progress has been made on CoV E, there is still much to be discovered about this small, enigmatic protein.

Poimin artiikelista mutamia lauseita E virusproteiinista joka voi muodostaa  jonikanavankin ja sen kauttta tuottaa  kalsiumijonia paikalle ja vapaana solunsisäisenä Ca++ on  "haitallinen" ja saattaa  solun tekemään päätöksiä tilanteen  hoitamiseksi Tässä virus käyttää tätä signaalia edukseen ja virioni tehtailunsa   edistämiseen.