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Ferreras, J.M. Ribosome-Inactivating Proteins. Encyclopedia. Available online: https://encyclopedia.pub/entry/7476 (accessed on 20 November 2024).
Ferreras JM. Ribosome-Inactivating Proteins. Encyclopedia. Available at: https://encyclopedia.pub/entry/7476. Accessed November 20, 2024.
Ferreras, José Miguel. "Ribosome-Inactivating Proteins" Encyclopedia, https://encyclopedia.pub/entry/7476 (accessed November 20, 2024).
Ferreras, J.M. (2021, February 22). Ribosome-Inactivating Proteins. In Encyclopedia. https://encyclopedia.pub/entry/7476
Ferreras, José Miguel. "Ribosome-Inactivating Proteins." Encyclopedia. Web. 22 February, 2021.
Ribosome-Inactivating Proteins
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This entry is adapted from the peer-reviewed paper 10.3390/toxins13020080

Ribosome-inactivating proteins (RIPs) are rRNA N-glycosylases from plants (EC 3.2.2.22) that inactivate ribosomes thus inhibiting protein synthesis.

adenine polynucleotide glycosylase antiviral therapy human virus immunotoxin

1. Introduction

One of the main efforts of virologists and molecular biologists is the search for antivirals that can help in the fight against viruses causing diseases in animals and especially in humans. Strategies are also being searched to tackle the challenge of plant viruses causing significant crop losses. This has led to the discovery of a number of antivirals with different chemical nature or proteins with different enzymatic activities [1][2]. The search for more effective and safer antivirals continues to be a field of intense investigation and plants are one of the most used sources, since they have evolved a variety of protein-based defense mechanisms to tackle viral infections [3]. Regarding ribosome-inactivating proteins (RIPs), it is worth noting the fact that one of the first RIPs to be purified was PAP (pokeweed antiviral protein) and although many RIPs have been purified as protein synthesis inhibitors, many others have been isolated as powerful antivirals. For many years, RIPs have been studied as potent inhibitors of protein synthesis that can be used for the construction of immunotoxins [4]. Since linked to a monoclonal antibody or a protein that specifically binds to a receptor, they can be used to specifically kill tumor cells [5][4]. RIPs have initially been studied as a family of proteins widely distributed among angiosperms although they have also been found in other taxons [6][7]. They irreversibly inactivate ribosomes inhibiting protein synthesis and thus causing cell death [6][7]. The first RIPs to be isolated, the extremely potent toxins ricin and abrin, were purified at the end of the nineteenth century and it was believed that their red cell agglutinating activity was the reason for the toxic effect [8][9]. In the early 1970s, it was reported that abrin, ricin, and PAP strongly inhibited protein synthesis in a cell-free rabbit reticulocyte system [8][9][10]; and Barbieri and Stirpe classified these and other related proteins as type 1 RIPs (a single polypeptide chain, such as PAP) and type 2 RIPs (two chains, an A chain similar to type 1 RIPs, and a B chain that possesses lectin activity, such as abrin and ricin) [4]. The enzymatic activity of ricin was discovered by Endo and colleagues, that is, RIPs are considered as 28S rRNA N-glycosylases (EC 3.2.2.22) that cleave the N-glycosidic bond between the adenine No. 4324 and its ribose in the 60S subunit of rat ribosomes [11] or the equivalent one in sensitive ribosomes from other organisms [12]. This adenine is located in the sarcin-ricin loop (SRL) that is crucial for anchoring the elongation factors EFG and EF2 on the ribosome during mRNA-tRNA translocation in prokaryotes and eukaryotes, respectively. This loop is also the target of ribotoxins such as α-sarcin, enzymes with rRNA endonuclease activity (EC 3.1.27.10) [13]. However, some RIPs are also able to remove more than an adenine from the rRNA [14] and many of them are able to deadenylate not only rRNA but also other polynucleotide substrates such as DNA, poly(A), mRNA, tRNA, and viral RNA [15], and because of this, the name of adenine polynucleotide glycosylase (or polynucleotide: adenosine glycosidase) was proposed for RIPs [15]. Additionally, other activities have been reported for RIPs, just as shown in Table 1.

Table 1. Proposed activities and other biological properties of ribosome-inactivating proteins (RIPs).

Activity Example of RIP
Agglutinin Ricin
Antiviral PAP
rRNA N-glycosylase Ricin
Adenine polynucleotide glycosylase Saporin-L1
rRNA N-glycosylase/lyase Gypsophilin/RALyase
RNase BBAP1
DNase BBAP1
Phosphatase Trichosanthin
Superoxide dismutase Camphorin
Phospholipase Ricin
Chitinase TKC 28-I
DNA nicking BE27
Apoptosis induction Stenodactylin
Necroptosis induction Stenodactylin
Autophagia induction Abrus Agglutinin
Senescence induction JIP60
Plant tissue necrosis JIP60

A convincing picture of the role played by these proteins in plants is not yet available. They seem to play different roles in different species, so antiviral, antifungal, plant defense, storage, programmed senescence, antifeedant, stress protection, and development regulation roles have been proposed for RIPs [7].

2. Activity on Animal (Human) Viruses

Global health threats such as the emergence of human viruses resistant to commonly used antiviral drugs, has prompted the study of RIPs as possible tools for fighting these agents. Antiviral activity of RIPs against different animal viruses has been reported (Table 2).

Table 2. RIPs active against animal viruses. RIPs with antiviral activity, the families and species from which they have been obtained and the viruses in which this activity has been demonstrated are shown.

Species and RIP Virus
POACEAE  
Zea mays L.  
Maize RIP HIV, SHIV
EUPHORBIACEAE  
Ricinus communis L.  
Ricin A chain HIV
Suregada multiflora (A.Juss.) Baill. (=Gelonium multiflorum A.Juss.)
Gelonin HIV, HPV, HSV, PICV,
GAP31 HIV
CUCURBITACEAE  
Trichosanthes kirilowii Maxim  
Trichosanthin (TCS) HBV, HIV, HSV
TAP29 HIV
Trichobitacin HIV
Momordica charantia L.  
Momordin (M. charantia inhibitor) HPV, HSV
Alpha-momorcharin (α-MMC) HBV, HIV, HSV
Beta-momorcharin HIV
Momordica antiviral protein (MAP30) DENV-2, HHV8, HBV, HIV, HSV
Momordica balsamina L.  
Balsamin HIV
Luffa cylindrica (L.) M.Roem.  
Luffin HIV
Bryonia cretica subsp. dioica (Jacq.) Tutin (=Bryonia dioica Jacq.)
Bryodin HIV
CARYOPHYLLACEAE  
Saponaria officinalis L.  
Saporin HIV
Dianthus caryophyllus L.  
Dianthin 32 (DAP32) HIV, HPV, HSV
Dianthin 30 (DAP30) HIV
Agrostemma githago L.  
Agrostin HIV
PHYTOLACCACEAE  
Phytolacca americana L.  
PAP (PAPI) CHIKV, FLUV, HBV, HIV, HPV,
  HSV, HTLV, JEV, LCMV
PAPII HIV
PAPIII HIV
PAP-S HSV, HPV, HBV

Virus name abbreviations: CHIKV (chikungunya virus), DENV (dengue virus), FLUV (human influenza virus), HBV (hepatitis B virus), HHV (human gammaherpesvirus), HIV (human immunodeficiency virus), HPV (human poliovirus), HSV (herpes simplex virus), HTLV (human T-cell leukemia virus), JEV (Japanese encephalitis virus), LCMV (lymphocytic choriomeningitis virus), PICV (Pichinde virus), SHIV (simian–human immunodeficiency virus).

RIPs with antiviral activity belong to the main types of RIPs found in angiosperms [7]: monocot type 1 RIPs (Poaceae), dicot type 1 RIPs (Euphorbiaceae, Caryophyllaceae, Phytolaccaceae), type 2 RIPs (ricin, Euphorbiaceae), and type 1 RIPs derived from type 2 RIPs (Cucurbitaceae); which suggests that all these proteins could have, to a greater or lesser extent, antiviral activity and that their main biological role could be precisely the defense of the plant against viruses. However, researchers have focused on the study of proteins obtained from species of the families Phytolaccaceae, Cucurbitaceae, Caryophyllaceae, and Euphorbiaceae; and the most studied RIPs are pokeweed antiviral protein (PAP), trichosanthin (TCS) and Momordica antiviral protein (MAP30), which have been the subject of recent reviews [10][35][36][38][58]. It is noteworthy that RIPs have shown to be active against viruses of very different nature: double-stranded (ds) DNA viruses (hepatitis B virus, HBV; human gammaherpesvirus, HHV; human poliovirus, HPV; herpes simplex virus, HSV), retroviruses (human immunodeficiency virus, HIV; human T-cell leukemia virus, HTLV; simian–human immunodeficiency virus, SHIV), positive-sense single-stranded (ss) RNA viruses (Japanese encephalitis virus, JEV; dengue virus, DENV; chikungunya virus, CHIKV), and negative-sense (ss) RNA viruses (human influenza virus, FLUV; lymphocytic choriomeningitis virus, LCMV; Pichinde virus, PICV). Most of the viruses studied are enveloped viruses that infect humans, with the exceptions of the simian–human immunodeficiency virus (SHIV), the Pichinde virus (PICV), and the non-enveloped human poliovirus. This virus was the first in which activity against an animal virus was reported [59]. Results obtained with HEp-2 cells infected with human poliovirus or herpes simplex virus (HSV) showed that gelonin, momordin, dianthin 32, and PAP-S impaired viral replication by inhibiting protein synthesis in virus-infected cells, in which presumably they enter more easily than in uninfected cells [30], suggesting that antiviral activity could be a general property of RIPs.

2.1. Activity on Human Immunodeficiency Virus

The most studied virus is the human immunodeficiency virus (HIV). The lack of effective antivirals against this virus and its rapid spread around the world prompted studies on the activity of RIPs against this virus since 1989 [60]. At least 20 RIPs have shown activity against HIV (Table 2). Thus, several RIPs obtained from Euphorbiaceae and Caryophylaceae, but mostly from Cucurbitaceae and Phytolocaceae, inhibit the replication of HIV in vitro [35]. It has also been reported that maize RIP transiently reduces viral load in SHIV infected Chinese rhesus macaques [27]. The results obtained with RIPs promoted their use in clinical trials [61]. Although the development of specific HIV antivirals such as reverse-transcriptase and protease inhibitors have directed AIDS therapy to other treatments, these studies demonstrated the potential of RIPs for the treatment of virus-related diseases.

2.2. Activity on Herpes Simplex Virus

Another virus that has been targeted by RIPs is the herpes simplex virus (HSV). Currently, there is no treatment that completely eliminates HSV infection from the body, because once the virus enters an organism, it remains dormant until reactivated. This has encouraged researchers to study RIPs as candidates for HSV therapy. Gelonin, trichosanthin, dianthin 32, PAP, PAP-S, and several RIPs obtained from Momordica charantia have shown anti-HSV activity in vitro (Table 2).

2.3. Activity on Other Animal Viruses

Exposure of HepG2.2.15 cells to MAP30 [44], PAP-S [56], α-momorcharin [41], and an eukaryotic expression plasmid encoding PAP [56] inhibits the production of hepatitis B virus (HBV). Additionally, an extract from Radix Trichosanthis had a stronger inhibitive effect on expression of HBsAg and HBeAg in HepG2.2.15, and trichosanthin has been proposed as the main component of the aqueous extract responsible for the anti-hepatitis B viral effect [62].

On the other hand, it has also been reported that PAP inhibits replication of human T-cell leukemia (HTLV), human influenza, chikungunya (CHIKV), Japanese encephalitis (JEV), and lymphocytic choriomeningitis (LCMV) viruses, gelonin inhibits Pichinde virus replication, and MAP30 inhibits human gammaherpesvirus 8 (HHV8) and dengue virus [10][31][35][42][52][53][54][55].

2.4. Citotoxicity of RIPs

An important aspect to consider when working with antivirals is their cytotoxicity. In this sense, type 1 RIPs and type 2 RIPs can be distinguished. Type 1 RIPs consist of a polypeptide chain with rRNA N-glycosylase activity, while type 2 RIPs are constituted by two chains linked by a disulfide bond: The A chain (active) is equivalent to a type 1 RIP and the B chain (binding) is a lectin able to bind to membrane glycoproteins and glycolipids allowing endocytosis of RIP by cells. This is why RIPs such as ricin and abrin are extremely toxic showing IC50 (concentration that inhibits protein synthesis by 50%) values of 0.67–8 pM in cell cultures [63]. There are type 2 RIPs such as those from Sambucus which are much less toxic to cultured cells with IC50 values of 27–64 nM [64]. Type 1 RIPs are much less toxic and have highly variable IC50 values (0.2–10 μM) [63]. Due to the high cytotoxicity of type 2 RIPs, only type 1 RIPs or the ricin A-chain (which has a cytotoxicity similar to that of type 1 RIPs) [63] have been used as antiviral agents.

A good antiviral should display a substantial difference between the antiviral concentration and the cytotoxic concentration. Due to the diverse toxicities of type 1 RIPs, there are also differences in this regard, but the most commonly used proteins such as PAP, MAP30, or trichosanthin always show a substantial difference between toxic concentrations for cells (3–30 μM) [63][65][66] and concentrations that have antiviral activity (around 30 nM) [35].

Finally, it should be noted that some bacterial and fungal enzymes targeting the sarcin-ricin loop have also been reported to possess antiviral activity [2][67][68][69][70][71][72][73].

Therefore, RIPs have awakened over many years, and continue to do so, a keen interest as tools to fight viruses that cause diseases in humans. In fact, recently saporin and RTAM-PAP1 (a chimera constructed with ricin A-chain and PAP) have been proposed as candidates for therapy of COVID-19 [74][75].

3. Activity against Plant Viruses

To date, 39 RIPs have been described that display some type of activity against plant viruses (Table 3).

Table 3. RIPs active against plant viruses. RIPs with antiviral activity, the families and species from which they have been obtained and the viruses in which this activity has been demonstrated are shown.

Species and RIP Virus
IRIDACEAE  
Iris x hollandica Tub.  
IRIP TMV, TEV
IRAb TMV, TEV
EUPHORBIACEAE  
Jatropha curcas L.  
Curcin 2 TMV
CUCURBITACEAE  
Trichosanthes kirilowii Maxim  
Trichosanthin TuMV, CMV, TMV
Momordica charantia L.  
α-Momorcharin CMV, ChiVMV, TMV, TuMV
LEGUMINOSAE  
Senna occidentalis (L.) Link (=Cassia occidentalis L.)
Cassin TMV
CARYOPHYLLACEAE  
Saponaria officinalis L.  
Saporin BMV, TMV, AMV
Dianthus caryophyllus L.  
Dianthin 30 ACMV, TMV
Dianthin 32 TMV
AMARANTHACEAE  
Beta vulgaris L.  
BE27 TMV, AMCV
Amaranthus tricolor L.  
AAP-27 SHMV
Amaranthus viridis L.  
Amaranthin TMV
Celosia argentea L. (=Celosia cristata L., = Celosia plumosa (Voss) Burv.)
CCP 25 BMV, PMV, TMV, SHMV, ICRSV
CCP 27 TMV, SHMV, ICRSV
Chenopodium album L.  
CAP-I TMV, SHMV
CAP-II TMV, SHMV
CAP30 TMV
Salsola longifolia Forssk.  
SLP-32 BYMV, TNV
Spinacia oleracea L.  
VI (SoRIP2) TMV
PHYTOLACCACEAE  
Phytolacca insularis Nakai  
PIP TMV, CMV, PVY, PVX, PLRV
Phytolacca dioica L.  
Dioicin 2 TMV
PD-S2 TMV
PD-L1 TNV
PD-L4 TMV, TNV
Phytolacca americana L.  
PAP (PAPI) BMV, TMV, AMV, TBSV, SPMV, ZYMV
  CMV, PVY, PVX, TEV, SBMV
PAPII TMV, PVX
PAP-S AMCV
NYCTAGINACEAE  
Boerhaavia diffusa L.  
BDP-30 TMV
Mirabilis expansa (Ruiz & Pav.) Standl.  
ME1 TMV, BMV
Mirabilis jalapa L.  
MAP TMV
Bougainvillea spectabilis Willd.  
Bouganin ZYMV, AMCV
Bougainvillea buttiana Holttum & Standl.  
BBAP1 SHMV
BBP-24 TMV, SHMV
BBP-28 TMV, SHMV
BASELLACEAE  
Basella alba L. (=Basella rubra L.)  
RIP2 AMCV
LAMIACEAE  
Volkameria inermis L. (=Clerodendrum inerme (L.) Gaertn.)
CIP-29 TMV, PRSV, SHMV
Volkameria aculeata L. (=Clerodendrum aculeatum (L.) Schltdl.)
CA-SRI (CAP-34) TMV, SHMV, PRSV
ADOXACEAE  
Sambucus nigra L.  
SNAI’ TMV
Nigrin b (SNAV) TMV

Virus name abbreviations: ACMV (African cassava mosaic virus), AMCV (artichoke mottled crinkle virus), AMV (alfalfa mosaic virus), BMV (brome mosaic virus), BYMV (bean yellow mosaic virus), ChiVMV (Chilli veinal mottle virus), CMV (cucumber mosaic virus), ICRSV (Indian citrus ringspot virus = citrus ringspot virus, CRSV), PLRV (potato leafroll virus), PMV (pokeweed mosaic virus), PRSV (papaya ringspot virus), PVX (potato virus X), PVY (potato virus Y), SBMV (southern bean mosaic virus), SHMV (sunn-hemp mosaic virus = sunn-hemp rosette virus, SRV), SPMV (satellite panicum mosaic virus), TBSV (tomato bushy stunt virus), TEV (tobacco etch virus), TMV (tobacco mosaic virus), TNV (tobacco necrosis virus), TuMV (turnip mosaic virus), ZYMV (zucchini yellow mosaic virus).

 

 

These RIPs have been found in 26 plant species belonging to one family of monocotyledons and ten families of dicotyledons, that are distributed throughout the phylogenetic tree of angiosperms in a similar way to the RIP-containing plants [7], thus suggesting that most RIPs could be active against plant viruses. As a matter of fact, only two type 2 RIPs from Sambucus nigra (SNAI and SNLRP) have been reported to fail to protect transgenic plants against viral infection [76].

Despite the fact that these antiviral proteins are distributed in a great variety of families, most of them (thirty one) belong to the orders Caryophyllales and Lamiales (families Caryophyllaceae, Amaranthaceae, Phytolaccaceae, Nyctaginaceae, Basellaceae, Lamiaceae), which are RIPs with well-defined structural and phylogenetic characteristics [7].

RIPs seem to be active against a wide range of viruses (Table 3), all of them belonging to different families of positive-sense single-stranded (ss) RNA viruses. The exception is the geminivirus ACMV (African cassava mosaic virus), which contains a single-stranded circular DNA genome. They seem to protect all kinds of plants and, although the most commonly used plant for testing has been Nicotiana tabacum L., RIPs have also shown ability to protect other species of the genus Nicotiana (N. benthamiana Domin and N. glutinosa L.) as well as other species commonly used in research or crops such as Brassica rapa L. (=B. parachinensis L.H.Bailey) (choy sum), Cyamopsis tetragonoloba (L.) Taub. (guar), Crotalaria juncea L. (sunn hemp). Phaseolus vulgaris L. (common bean), Momordica charantia L. (bitter melon), Beta vulgaris L. (sugar beet), Cucurbita pepo L. (squash), Solanum tuberosum L. (potato), Carica papaya L. (papaya), Chenopodium quinoa Willd. (quinoa), or Lycopersicon esculentum Mill. (tomato).

It is difficult to compare the antiviral activity of the different RIPs because different criteria have been used to evaluate their antiviral capacity. In some cases, the putative antiviral character is based on their N-glycosylase activity on the virus genome [105]; all RIPs are able to release adenines from any kind of RNA or DNA, including viral genomes [4]. This adenine polynucleotide glycosylase activity has been detected by electrophoresis [87], or HPLC [103][105]. In many cases, the test has involved applying a RIP solution on the leaf surface of the plant together with the virus and comparing the result with the control that does not contain RIP. In some cases, the virus is applied simultaneously [86][92][113] and in others, sometime after the application of the RIP [90][115]. The evaluation of antiviral activity has been done by counting the number of lesions [88][93], the time of onset of symptoms [77][79], the number of infected plants [105], or the severity of the infection symptoms [78][115]. Virus levels have also been estimated by ELISA [99], Western blotting analysis [81], RT-PCR analysis [101], quantitative real-time PCR analysis [81][82], electron microscopy [92], or by determining the infection capacity of an extract from the infected plant [92]. Another approach has been the construction of virus-resistant transgenic plants [80][102]. The virus has been inoculated mechanically or by aphids [102] and the resistance has been determined by one of the methods listed above.

Other studies link RIPs to the defense of plants against viruses, especially studies of induction of RIPs through signaling compounds such as salicylic acid, hydrogen peroxide, or jasmonic acid, which are involved in the systemic acquired resistance (SAR) of plants against viruses and other pathogens. Thus, it has been reported that artichoke mottled crinkle virus (AMCV), salicylic acid, and hydrogen peroxide induce the expression of BE27 in both treated and untreated leaves of sugar beet plant [86][117]. On the other hand, it has been reported that alpha-momorcharin induces the generation of salicylic acid, jasmonic acid, and reactive oxygen species, which improve tobacco mosaic virus (TMV) tolerance [118]. Additionally, alpha-momorcharin induces the expression of the N gene [118], which encodes the N protein that recognizes the TMV replicase fragment and triggers signal transduction cascades, initiating a hypersensitive response (HR) and inhibiting the spread of TMV [118]. Other RIPs in which some type of elicitor activity has been reported are pokeweed antiviral protein II (PAPII) [104], CIP-29 [111], and CA-SRI [113][115]. By contrast, the antiviral activity of SNAI’ [116], IRIP and IRAb [77], and nigrin b [76] is not accompanied by an induction of pathogenesis-related proteins. All this suggests that some, but not all RIPs, could be part of the SAR or/and HR to defend the plant against viral infections.

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Subjects: Biochemistry & Molecular Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
José Miguel Ferreras
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Update Date: 25 Feb 2021
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