Dataset Information

Integrative proteome and acetylome analyses of murine responses to Cryptococcus neoformans infection

ABSTRACT: Cryptococcus neoformans, an environmental opportunistic human fungal pathogen, is a causative agent for acute pulmonary infection and meningoencephalitis. Understanding the host’s response to C. neoformans infection is critical for developing effective treatment. Even though some have elucidated the host response at the transcriptome level, little is known about how it modulates its defense machinery through the proteome mechanism or how protein posttranslational modification responds to the infection. In this work, we employed a Cryptococcus murine infection model and mass spectrometry to systematically determine the proteome and acetylome statuses of two primary organs (lung and brain) in the early stage of infection. To extensively analyze the host response, we compared and integrated the proteome data to the transcriptome results. We demonstrated a significant overlap between two data sets. Critical genes, including genes involved in phagosome, lysosome, or osteoblast differentiation and platelet activation are significantly altered in protein and gene expression during infection. In the acetylome analysis, we demonstrated that lung and brain tissues differentially regulate protein acetylation during infection. The three primary groups of proteins altered in acetylation status are histones, proteins involved in glucose and fatty acid metabolism, and proteins from the immune system. These analyses provide an integrative regulation network of the host responding to C. neoformans and shed new light on understanding the host’s regulation mechanism when responding to C. neoformans.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Lung

DISEASE(S): Cryptococcal Meningitis

SUBMITTER: Hai-Long Li

LAB HEAD: Chen Ding

PROVIDER: PXD016614 | Pride | 2020-04-21

REPOSITORIES: Pride

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Publications

Integrative Proteome and Acetylome Analyses of Murine Responses to Cryptococcus neoformans Infection.

Li Hailong H Li Yanjian Y Sun Tianshu T Du Wei W Zhang Zhijie Z Li Dancheng D Ding Chen C

Frontiers in microbiology 20200417

Cryptococcus neoformans is a causative agent for pulmonary infection and meningoencephalitis. Understanding the host's response to C. neoformans infection is critical for developing effective treatment. Even though some have elucidated the host response at the transcriptome level, little is known about how it modulates its defense machinery through the proteome mechanism or how protein posttranslational modification responds to the infection. In this work, we employed a murine infe ...[more]

PMID: 32362878

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Project description:Ubiquitination is a reversible protein modification involved in various cellular processes in eukaryotic cells. Deubiquitinating enzymes, the proteins responsible for the removal of ubiquitin, act as essential regulators to maintain ubiquitin homeostasis and to exquisitely regulate protein degradation via the ubiquitination pathway. Cryptococcus neoformans is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily within the immunocompromised population. In order to understand the possible influence deubiquitinating enzymes have on growth and virulence of the model pathogenic yeast Cryptococcus neoformans, we generated deletion mutants of 7 putative deubiquitinase genes. Compared to other deubiquitinating enzyme mutants, a ubp5M-bM-^HM-^F mutant exhibited severely attenuated virulence and many distinct phenotypes, including decreased capsule formation, hypomelanization, defective sporulation, and elevated sensitivity to several external stressors (such as high temperature, oxidative and nitrosative stresses, high salts, and antifungal agents). Ubp5 appears to be the major deubiquitinating enzyme in C. neoformans for maintaining a pool of free ubiquitin for stress responses, supports the evolutionary divergence of Cryptococcus sp. from the model yeast S. cerevisiae, and provides an important paradigm for understanding the potential role of deubiquitination in virulence by other pathogenic fungi. In addition, other putative deubiquitinase mutants (doa4M-bM-^HM-^F and ubp13M-bM-^HM-^F) exhibit similar phenotypes to the ubp5M-bM-^HM-^F mutant, illustrating possible functional overlap among deubiquitinating enzymes in C. neoformans. Certain functioning deubiquitinating enzymes are essential for the virulence composite of C. neoformans and provide an additional yeast survival and propagation advantage in the host. WT Cryptococcus neoformans strain H99 was incubated in pooled ex vivo human CSF obtained from de-identified patients and harvested after 24hr for RNA extraction. New Zealand White rabbits were inoculated with WT strain H99 and harvested by intracisternal spinal tap on days 1 and 7 for RNA extraction.

Project description:Ubiquitination is a reversible protein modification involved in various cellular processes in eukaryotic cells. Deubiquitinating enzymes, the proteins responsible for the removal of ubiquitin, act as essential regulators to maintain ubiquitin homeostasis and to exquisitely regulate protein degradation via the ubiquitination pathway. Cryptococcus neoformans is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily within the immunocompromised population. In order to understand the possible influence deubiquitinating enzymes have on growth and virulence of the model pathogenic yeast Cryptococcus neoformans, we generated deletion mutants of 7 putative deubiquitinase genes. Compared to other deubiquitinating enzyme mutants, a ubp5∆ mutant exhibited severely attenuated virulence and many distinct phenotypes, including decreased capsule formation, hypomelanization, defective sporulation, and elevated sensitivity to several external stressors (such as high temperature, oxidative and nitrosative stresses, high salts, and antifungal agents). Ubp5 appears to be the major deubiquitinating enzyme in C. neoformans for maintaining a pool of free ubiquitin for stress responses, supports the evolutionary divergence of Cryptococcus sp. from the model yeast S. cerevisiae, and provides an important paradigm for understanding the potential role of deubiquitination in virulence by other pathogenic fungi. In addition, other putative deubiquitinase mutants (doa4∆ and ubp13∆) exhibit similar phenotypes to the ubp5∆ mutant, illustrating possible functional overlap among deubiquitinating enzymes in C. neoformans. Certain functioning deubiquitinating enzymes are essential for the virulence composite of C. neoformans and provide an additional yeast survival and propagation advantage in the host. New Zealand White rabbits were inoculated with WT strain H99 and harvested by intracisternal spinal tap on days 1, 3, 4, and 7. For the human sample, RNA was extracted from CSF obtained from a de-identified patient with cryptococcal meningitis.

Dataset Information

Integrative proteome and acetylome analyses of murine responses to Cryptococcus neoformans infection

Publications

Integrative Proteome and Acetylome Analyses of Murine Responses to <i>Cryptococcus neoformans</i> Infection.

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