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Toward more accurate prediction of caspase cleavage sites: a comprehensive review of current methods, tools and features.

ABSTRACT: As one of the few irreversible protein posttranslational modifications, proteolytic cleavage is involved in nearly all aspects of cellular activities, ranging from gene regulation to cell life-cycle regulation. Among the various protease-specific types of proteolytic cleavage, cleavages by casapses/granzyme B are considered as essential in the initiation and execution of programmed cell death and inflammation processes. Although a number of substrates for both types of proteolytic cleavage have been experimentally identified, the complete repertoire of caspases and granzyme B substrates remains to be fully characterized. To tackle this issue and complement experimental efforts for substrate identification, systematic bioinformatics studies of known cleavage sites provide important insights into caspase/granzyme B substrate specificity, and facilitate the discovery of novel substrates. In this article, we review and benchmark 12 state-of-the-art sequence-based bioinformatics approaches and tools for caspases/granzyme B cleavage prediction. We evaluate and compare these methods in terms of their input/output, algorithms used, prediction performance, validation methods and software availability and utility. In addition, we construct independent data sets consisting of caspases/granzyme B substrates from different species and accordingly assess the predictive power of these different predictors for the identification of cleavage sites. We find that the prediction results are highly variable among different predictors. Furthermore, we experimentally validate the predictions of a case study by performing caspase cleavage assay. We anticipate that this comprehensive review and survey analysis will provide an insightful resource for biologists and bioinformaticians who are interested in using and/or developing tools for caspase/granzyme B cleavage prediction.

SUBMITTER: Bao Y

PROVIDER: S-EPMC6917222 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Toward more accurate prediction of caspase cleavage sites: a comprehensive review of current methods, tools and features.

Bao Yu Y Marini Simone S Tamura Takeyuki T Kamada Mayumi M Maegawa Shingo S Hosokawa Hiroshi H Song Jiangning J Akutsu Tatsuya T

Briefings in bioinformatics 20190901 5

As one of the few irreversible protein posttranslational modifications, proteolytic cleavage is involved in nearly all aspects of cellular activities, ranging from gene regulation to cell life-cycle regulation. Among the various protease-specific types of proteolytic cleavage, cleavages by casapses/granzyme B are considered as essential in the initiation and execution of programmed cell death and inflammation processes. Although a number of substrates for both types of proteolytic cleavage have ...[more]

PMID: 29860277

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Project description:BackgroundCaspases are a family of proteases that have central functions in programmed cell death (apoptosis) and inflammation. Caspases mediate their effects through aspartate-specific cleavage of their target proteins, and at present almost 400 caspase substrates are known. There are several methods developed to predict caspase cleavage sites from individual proteins, but currently none of them can be used to predict caspase cleavage sites from multiple proteins or entire proteomes, or to use several classifiers in combination. The possibility to create a database from predicted caspase cleavage products for the whole genome could significantly aid in identifying novel caspase targets from tandem mass spectrometry based proteomic experiments.ResultsThree different pattern recognition classifiers were developed for predicting caspase cleavage sites from protein sequences. Evaluation of the classifiers with quality measures indicated that all of the three classifiers performed well in predicting caspase cleavage sites, and when combining different classifiers the accuracy increased further. A new tool, Pripper, was developed to utilize the classifiers and predict the caspase cut sites from an arbitrary number of input sequences. A database was constructed with the developed tool, and it was used to identify caspase target proteins from tandem mass spectrometry data from two different proteomic experiments. Both known caspase cleavage products as well as novel cleavage products were identified using the database demonstrating the usefulness of the tool. Pripper is not restricted to predicting only caspase cut sites, but it gives the possibility to scan protein sequences for any given motif(s) and predict cut sites once a suitable cut site prediction model for any other protease has been developed. Pripper is freely available and can be downloaded from http://users.utu.fi/mijopi/Pripper.ConclusionsWe have developed Pripper, a tool for reading an arbitrary number of proteins in FASTA format, predicting their caspase cleavage sites and outputting the cleaved sequences to a new FASTA format sequence file. We show that Pripper is a valuable tool in identifying novel caspase target proteins from modern proteomics experiments.

Project description:Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causative agent of three hyperproliferative disorders: Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. During viral latency a small subset of viral genes are produced, including KSHV latency-associated nuclear antigen (LANA), which help the virus thwart cellular defense responses. We found that exposure of KSHV-infected cells to oxidative stress, or other inducers of apoptosis and caspase activation, led to processing of LANA and that this processing could be inhibited with the pan-caspase inhibitor Z-VAD-FMK. Using sequence, peptide, and mutational analysis, two caspase cleavage sites within LANA were identified: a site for caspase-3 type caspases at the N-terminus and a site for caspase-1 and-3 type caspases at the C-terminus. Using LANA expression plasmids, we demonstrated that mutation of these cleavage sites prevents caspase-1 and caspase-3 processing of LANA. This indicates that these are the principal sites that are susceptible to caspase cleavage. Using peptides spanning the identified LANA cleavage sites, we show that caspase activity can be inhibited in vitro and that a cell-permeable peptide spanning the C-terminal cleavage site could inhibit cleavage of poly (ADP-ribose) polymerase and increase viability in cells undergoing etoposide-induced apoptosis. The C-terminal peptide of LANA also inhibited interleukin-1 beta (IL-1β) production from lipopolysaccharide-treated THP-1 cells by more than 50%. Furthermore, mutation of the two cleavage sites in LANA led to a significant increase in IL-1β production in transfected THP-1 cells; this provides evidence that these sites function to blunt the inflammasome, which is known to be activated in latently infected PEL cells. These results suggest that specific caspase cleavage sites in KSHV LANA function to blunt apoptosis as well as interfere with the caspase-1-mediated inflammasome, thus thwarting key cellular defense mechanisms.

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Toward more accurate prediction of caspase cleavage sites: a comprehensive review of current methods, tools and features.

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Toward more accurate prediction of caspase cleavage sites: a comprehensive review of current methods, tools and features.

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