Dataset Information

Proteome remodeling in the Mycobacterium tuberculosis PknG knockout: molecular hints for the role of this kinase in cell envelope biogenesis and hypoxia.

ABSTRACT: Tuberculosis, a pulmonary disease caused by the etiological agent Mycobacterium tuberculosis, is the leading cause of death by a single infectious agent among human beings. One of M. tuberculosis's pathogenic hallmarks is its ability to persist in a dormant state in the host for long periods, reinitiating the infectious cycle when favorable environmental conditions are found. Thus, it is not surprising that this pathogen has developed different mechanisms to withstand the stressful conditions found in the host. In particular, the Ser/Thr protein kinase PknG has gained special relevance since it regulates nitrogen metabolism and facilitates bacterial survival inside macrophages. Nevertheless, the molecular mechanisms underlying these effects are far from being elucidated. To further investigate these issues, we performed quantitative proteomics analyses of protein extracts from M. tuberculosis H37Rv and a mutant derivative lacking PknG. Our results show that in the absence of PknG the mycobacterial proteome was remodeled since 6.5% of the proteins encoded by M. tuberculosis presented significant changes in its relative abundance when compared to the wild-type strain. The main biological processes affected by PknG deletion were the biosynthesis of cell envelope components and the response to hypoxic conditions. Altogether, the results presented here allow us to postulate that PknG regulation of bacterial fitness to stress conditions in host macrophages might be an essential mechanism underlying its reported effect on intracellular bacterial survival.

INSTRUMENT(S): LTQ

ORGANISM(S): Mycobacterium Tuberculosis H37rv

TISSUE(S): Protein

DISEASE(S): Tuberculosis

SUBMITTER: Analía Lima

LAB HEAD: Rosario Durán

PROVIDER: PXD023975 | Pride | 2021-06-02

REPOSITORIES: Pride

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Proteome remodeling in the Mycobacterium tuberculosis PknG knockout: Molecular evidence for the role of this kinase in cell envelope biogenesis and hypoxia response.

Lima Analía A Leyva Alejandro A Rivera Bernardina B Portela María Magdalena MM Gil Magdalena M Cascioferro Alessandro A Lisa María-Natalia MN Wehenkel Annemarie A Bellinzoni Marco M Carvalho Paulo C PC Batthyány Carlos C Alvarez María N MN Brosch Roland R Alzari Pedro M PM Durán Rosario R

Journal of proteomics 20210524

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is among the deadliest human pathogens. One of M. tuberculosis's pathogenic hallmarks is its ability to persist in a dormant state in the host. Thus, this pathogen has developed mechanisms to withstand stressful conditions found in the human host. Particularly, the Ser/Thr-protein kinase PknG has gained relevance since it regulates nitrogen metabolism and facilitates bacterial survival inside macrophages. Nevertheless, the molecu ...[more]

PMID: 34044169

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Project description:The thymus is one of the most affected organs during malnutrition, exhibiting atrophy and thymocyte depletion, characteristics that are also observed in several infectious diseases. The detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). However, the thymus has been barely studied during malnutrition and Leishmania infantum infection association. Protein malnutrition modifies intrathymic communication in L. infantum infected BALB/c mice by altering the abundance of proteins secreted to the thymic interstitial fluid (IF). We identified and compared protein abundance in the thymic IF samples from BALB/c mice that were fed with control protein (14%, CP) or low protein (4%, LP) isocaloric diets, followed by infection with L. infantum. By means of a quantitative proteomics approach using iTRAQ we identified 280 proteins of which 81% were reported as secreted by exosomes and 42% were previously described as secreted by thymic epithelial cells. LP-infected (LPi) animals showed a significant decrease in exosomal proteins, suggesting that exosomal carrier system is dysregulated in malnourished animals. LPi mice also exhibited an increase in the relative abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed that protein malnutrition decreases the proliferation of single positive and double positive T cells. Proteins engaged in glycolysis, protein ubiquitination and mRNA processing were significantly decreased. In addition, a significant decrease in the abundance of galectin-1 and increase of plasminogen were observed in malnourished animals. Together, the reduced cortical area, decreased proliferation, increased abundance of lipid- and tricarboxylic acid cycle-related proteins, and altered abundance of galectin-1 and plasminogen indicate a dysfunctional thymic microenvironment, where T cell migration, proliferation and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.

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