Inteins in pathogenic fungi: a phylogenetic tool and perspectives for therapeutic applications

Theodoro, Raquel Cordeiro; Bagagli, Eduardo

doi:10.1590/s0074-02762009000300017

Cited by 9 publications

(3 citation statements)

References 58 publications

(53 reference statements)

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“…In mini-inteins, HE domains are supposed to be completely deleted. In addition, their location in highly conserved genes facilitates the design of primers for their amplification ( Butler and Poulter, 2005 ; Theodoro and Bagagli, 2009 ; Prandini et al, 2013 ).…”

Section: Types Of Inteins and How They Operatementioning

confidence: 99%

Evolution and Application of Inteins in Candida species: A Review

et al. 2016

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Inteins are invasive intervening sequences that perform an autocatalytic splicing from their host proteins. Among eukaryotes, these elements are present in many fungal species, including those considered opportunistic or primary pathogens, such as Candida spp. Here we reviewed and updated the list of Candida species containing inteins in the genes VMA, THRRS and GLT1 and pointed out the importance of these elements as molecular markers for molecular epidemiological researches and species-specific diagnosis, since the presence, as well as the size of these inteins, is polymorphic among the different species. Although absent in Candida albicans, these elements are present in different sizes, in some environmental Candida spp. and also in most of the non-albicans Candida spp. considered emergent opportunistic pathogens. Besides, the possible role of these inteins in yeast physiology was also discussed in the light of the recent findings on the importance of these elements as post-translational modulators of gene expression, reinforcing their relevance as alternative therapeutic targets for the treatment of non-albicans Candida infections, because, once the splicing of an intein is inhibited, its host protein, which is usually a housekeeping protein, becomes non-functional.

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Section: Types Of Inteins and How They Operatementioning

confidence: 99%

Evolution and Application of Inteins in Candida species: A Review

et al. 2016

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“…Pathogenic fungi seem to be enriched for inteins [27,28]. Several notable human pathogens contain Prp8 inteins, including Aspergillus fumigatus , Histoplasma capsulatum , and Cryptococcus neoformans ( Cne ).…”

Section: Introductionmentioning

confidence: 99%

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

Green

Smith

et al. 2019

PLoS Biol

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The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNAs. At its functional core lies the essential pre-mRNA processing factor 8 (Prp8) protein. Across diverse eukaryotes, this protein cofactor of RNA catalysis harbors a self-splicing element called an intein. Inteins in Prp8 are extremely pervasive and are found at 7 different sites in various species. Here, we focus on the Prp8 intein from Cryptococcus neoformans (Cne), a human fungal pathogen. We solved the crystal structure of this intein, revealing structural homology among protein splicing sequences in eukaryotes, including the Hedgehog C terminus. Working with the Cne Prp8 intein in a reporter assay, we find that the biologically relevant divalent metals copper and zinc inhibit intein splicing, albeit by 2 different mechanisms. Copper likely stimulates reversible modifications on a catalytically important cysteine, whereas zinc binds at the terminal asparagine and the same critical cysteine. Importantly, we also show that copper treatment inhibits Prp8 protein splicing in Cne. Lastly, an intein-containing Prp8 precursor model is presented, suggesting that metal-induced protein splicing inhibition would disturb function of both Prp8 and the spliceosome. These results indicate that Prp8 protein splicing can be modulated, with potential functional implications for the spliceosome.

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“…Pathogenic fungi seem to be enriched for inteins (27,28). Several notable human pathogens contain Prp8 inteins, including Aspergillus fumigatus, Histoplasma capsulatum, and Cryptococcus neoformans.…”

Section: Introductionmentioning

confidence: 99%

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

Green

Новикова

et al. 2018

Preprint

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protein splicing 15 16 * Corresponding authors: Marlene Belfort (mbelfort@albany.edu) or Hongmin Li 17 (hongmin.li@health.ny.gov) 18 ABSTRACT 19The spliceosome is a large ribonucleoprotein complex that removes introns from 20 pre-mRNAs. At its functional core lies the essential Prp8 protein. Across diverse 21 eukaryotes, this protein cofactor of RNA catalysis harbors a self-splicing element, called 22 an intein. Inteins in Prp8 are extremely pervasive and are found at seven different sites in 23 various species. Here, we focus on the Prp8 intein from Cryptococcus neoformans, a 24 human fungal pathogen. We solved the crystal structure of this intein, revealing structural 25 homology among self-splicing sequences in eukaryotes, including Hedgehog protein. 26Working with the C. neoformans Prp8 intein in a reporter assay, we find that the 27 biologically relevant divalent metals copper and zinc inhibit intein splicing, albeit by two 28 different mechanisms. Copper likely stimulates reversible modifications on a catalytically 29 important cysteine, whereas zinc binds via the same critical cysteine with a Kd of ~1 nM. 30An intein-containing Prp8 precursor model is presented, suggesting that metal-induced 31 protein splicing inhibition would disturb function of both Prp8 and the spliceosome. 32These results indicate that Prp8 protein splicing can be modulated, and that this could 33 alter spliceosome function and RNA splicing under specific conditions. 34 nuclear and chloroplast genomes with distinct patterns of insertion (27). Nuclear inteins 58 tend to be in proteins that are involved in energy metabolism and RNA processing, 59whereas chloroplast inteins are found in proteins that carry out transcription and 60replication. Out of all the intein-harboring proteins in eukaryotes, Prp8 is 61 overwhelmingly favored. There are over one hundred inteins identified across various 62 sites of Prp8 in different species. 63Pathogenic fungi seem to be enriched for inteins (27, 28). Several notable human 64 pathogens contain Prp8 inteins, including Aspergillus fumigatus, Histoplasma 65 capsulatum, and Cryptococcus neoformans. Intriguingly, many organisms with Prp8 66inteins also tend to be intron-rich (29). The presence of inteins in Prp8 and the correlation 67 with intron density beg the question of an intein benefit to the host, and especially to 68 pathogens. To begin to answer this question, we focus on the Prp8 intein from C. 69 neoformans. This is a mini-intein, naturally lacking the homing endonuclease domain, at 70 only 171 amino acid residues. The intein is also found at a highly conserved site at the 71 center of Prp8, and thus is at the core of the spliceosome (1, 5, 30). 72 Studying the Prp8 intein present in C. neoformans addresses questions of 73 conditional protein splicing in an important human pathogen in an entirely new domain 74 of life. Solving the Prp8 intein structure set the stage for beginning such studies and 75 provided evolutionary context, by revealing similarities to the metazoan Hedgehog 76 protein. B...

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Inteins in pathogenic fungi: a phylogenetic tool and perspectives for therapeutic applications

Abstract: Inteins or "internal proteins" are coding sequences that are transcribed and translated with flanking sequences (exteins)

Cited by 9 publications

References 58 publications

Evolution and Application of Inteins in Candida species: A Review

Evolution and Application of Inteins in Candida species: A Review

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

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