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      Proteome-Wide Identification of Lysine Propionylation in the Conidial and Mycelial Stages of Trichophyton rubrum

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          Abstract

          Posttranslational modifications (PTMs) exist in a wide variety of organisms and play key roles in regulating various essential biological processes. Lysine propionylation is a newly discovered PTM that has rarely been identified in fungi. Trichophyton rubrum ( T. rubrum) is one of the most common fungal pathogens in the world and has been studied as an important model organism of anthropic pathogenic filamentous fungi. In this study, we performed a proteome-wide propionylation analysis in the conidial and mycelial stages of T. rubrum. A total of 157 propionylated sites on 115 proteins were identified, and the high confidence of propionylation identification was validated by parallel reaction monitoring (PRM) assay. The results show that the propionylated proteins were mostly involved in various metabolic pathways. Histones and 15 pathogenicity-related proteins were also targets for propionylation modification, suggesting their roles in epigenetic regulation and pathogenicity. A comparison of the conidial and mycelial stages revealed that most propionylated proteins and sites were growth-stage specific and independent of protein abundance. Based on the function classifications, the propionylated proteins had a similar distribution in both stages; however, some differences were also identified. Furthermore, our results show that the concentration of propionyl-CoA had a significant influence on the propionylation level. In addition to the acetylation, succinylation and propionylation identified in T. rubrum, 26 other PTMs were also found to exist in this fungus. Overall, our study provides the first global propionylation profile of a pathogenic fungus. These results would be a foundation for further research on the regulation mechanism of propionylation in T. rubrum, which will enhance our understanding of the physiological features of T. rubrum and provide some clues for the exploration of improved therapies to treat this medically important fungus.

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          Most cited references50

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          PLMD: An updated data resource of protein lysine modifications.

          Post-translational modifications (PTMs) occurring at protein lysine residues, or protein lysine modifications (PLMs), play critical roles in regulating biological processes. Due to the explosive expansion of the amount of PLM substrates and the discovery of novel PLM types, here we greatly updated our previous studies, and presented a much more integrative resource of protein lysine modification database (PLMD). In PLMD, we totally collected and integrated 284,780 modification events in 53,501 proteins across 176 eukaryotes and prokaryotes for up to 20 types of PLMs, including ubiquitination, acetylation, sumoylation, methylation, succinylation, malonylation, glutarylation, glycation, formylation, hydroxylation, butyrylation, propionylation, crotonylation, pupylation, neddylation, 2-hydroxyisobutyrylation, phosphoglycerylation, carboxylation, lipoylation and biotinylation. Using the data set, a motif-based analysis was performed for each PLM type, and the results demonstrated that different PLM types preferentially recognize distinct sequence motifs for the modifications. Moreover, various PLMs synergistically orchestrate specific cellular biological processes by mutual crosstalks with each other, and we totally found 65,297 PLM events involved in 90 types of PLM co-occurrences on the same lysine residues. Finally, various options were provided for accessing the data, while original references and other annotations were also present for each PLM substrate. Taken together, we anticipated the PLMD database can serve as a useful resource for further researches of PLMs. PLMD 3.0 was implemented in PHP + MySQL and freely available at http://plmd.biocuckoo.org.
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            Histone propionylation is a mark of active chromatin

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              Mutation in the Squalene Epoxidase Gene of Trichophyton interdigitale and Trichophyton rubrum Associated with Allylamine Resistance

              Dermatophytosis, the commonest superficial fungal infection, has gained recent attention due to its change of epidemiology and treatment failures. Despite the availability of several agents effective against dermatophytes, the incidences of chronic infection, reinfection, and treatment failures are on the rise. Trichophyton rubrum and Trichophyton interdigitale are the two species most frequently identified among clinical isolates in India. Consecutive patients ( n = 195) with suspected dermatophytosis during the second half of 2014 were included in this study. Patients were categorized into relapse and new cases according to standard definitions. Antifungal susceptibility testing of the isolated Trichophyton species ( n = 127) was carried out with 12 antifungal agents: fluconazole, voriconazole, itraconazole, ketoconazole, sertaconazole, clotrimazole, terbinafine, naftifine, amorolfine, ciclopirox olamine, griseofulvin, and luliconazole. The squalene epoxidase gene was evaluated for mutation (if any) in 15 T. interdigitale and 5 T. rubrum isolates exhibiting high MICs for terbinafine. A T1189C mutation was observed in four T. interdigitale and two T. rubrum isolates. This transition leads to the change of phenylalanine to leucine in the 397th position of the squalene epoxidase enzyme. In homology modeling the mutant residue was smaller than the wild type and positioned in the dominant site of squalene epoxidase during drug interaction, which may lead to a failure to block the ergosterol biosynthesis pathway by the antifungal drug.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                13 November 2019
                2019
                : 10
                : 2613
                Affiliations
                NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing, China
                Author notes

                Edited by: Dimitris G. Hatzinikolaou, National and Kapodistrian University of Athens, Greece

                Reviewed by: Jinkui Yang, Yunnan University, China; Jing Han, Institute of Microbiology (CAS), China

                *Correspondence: Tao Liu, liutao@ 123456ipbcams.ac.cn

                This article was submitted to Systems Microbiology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2019.02613
                6861857
                2e77ef19-7aa2-4118-97fd-f26ef4760df3
                Copyright © 2019 Xu, Cao, Yang, Chen, Liu, Liu and Jin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 July 2019
                : 28 October 2019
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 63, Pages: 16, Words: 0
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                dermatophytes,trichophyton rubrum (t. rubrum),posttranslational modifications (ptms),lysine propionylation,proteome

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