<i>Pneumocystis carinii</i> Expresses an Active Rtt109 Histone Acetyltransferase

Kottom, Theodore J.; Han, Junhong; Zhang, Zhiguo; Limper, Andrew H.

doi:10.1165/rcmb.2009-0443oc

Cited by 14 publications

(11 citation statements)

References 54 publications

(92 reference statements)

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“…Our laboratory has shown previously that P. carinii life forms express cell wall-remodeling transcripts differently based on the environmental conditions that they are exposed to (33,34,53). Therefore, we addressed whether Pckre6 expression was also regulated by environmental pH, examining a pH range of 4 to 8.…”

Section: Resultsmentioning

confidence: 99%

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

et al. 2015

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Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall ␤-glucans in stimulating inflammatory responses. Fungal ␤-glucans are comprised of D-glucose homopolymers containing ␤-1,3-linked glucose backbones with ␤-1,6-linked glucose side chains. Prior studies in Pneumocystis carinii have characterized ␤-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for ␤-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize ␤-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific ␤-1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 (Pckre6) ␤-1,6 glucan synthase in Pneumocystis that, when expressed in kre6-deficient Saccharomyces cerevisiae, restored cell wall stability. Recently synthesized ␤-1,6 glucan synthase inhibitors decreased the ability of isolated P. carinii preparations to generate ␤-1,6 carbohydrate. In addition, isolated ␤-1,6 glucan fractions from Pneumocystis elicited vigorous tumor necrosis factor alpha (TNF-␣) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that ␤-1,6 glucans are present in the P. carinii cell wall and contribute to lung cell inflammatory activation during infection. P neumocystis organisms are opportunistic fungi that produce significant morbidity and mortality in immunocompromised hosts, with infection-related fatalities ranging between 10% and 45% (1). Pneumocystis jirovecii is the species known to infect humans, while Pneumocystis carinii represents the parallel species studied widely in rodents (2). Pneumocystis pneumonia remains a significant cause of mortality during AIDS, despite highly active antiretroviral therapy (3-5). Severe Pneumocystis pneumonia is characterized by intense lung inflammation involving CD8 ϩ cells and neutrophils, impairing gas exchange (6-9).The P. carinii cell walls contain abundant ␤-glucan molecules (10). Fungal cell wall ␤-glucans are homopolymers of D-glucose consisting of ␤-1,3 core chains with variable numbers of ␤-1,6 glucose side chains. The variable inflammatory activities of different glucan preparations have been postulated to be related to the relative amounts and configurations of these two major structures (␤-1,3 versus ␤-1,6) (11). Almost all of the initial studies in fungi have largely focused on unfractionated glucans (10). In fact, all prior studies in P. carinii previously utilized only unfractionated ␤-1,3/␤-1,6 glucans. Interestingly, recent investigations in Saccharomyces cerevisiae indicate major roles for ␤-1,6 glucans in strongly mediating cellular activation and inflammation (11). Our investigations of unfractionated P. carinii ␤-glucans indicate that innate ...

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Section: Resultsmentioning

confidence: 99%

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

et al. 2015

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“…The cDNA was then cloned into the yeast pYES2.1 TOPO or pGEX-4T1 bacterial expression vector. Induction of gene expression in both bacteria and yeast has been described previously (30).…”

Section: Methodsmentioning

confidence: 99%

“…We obtained clinical waste BAL fluid samples after all clinical diagnostic testing had been performed. We used the entire residual samples (generally Ͻ5 ml) to isolate P. jirovecii organisms, as described previously (30). The entire P. jirovecii isolate was lysed in toto, and nucleic acids were extracted.…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant Schizosaccharomyces pombe Rtt109 (SpRtt109), PjRtt109, PcRtt109, REG␣, and glutathione S-transferase (GST) proteins were produced using standard procedures (30,31). Briefly, full-length cDNAs were amplified from cDNA using Pfu DNA polymerase.…”

Section: Methodsmentioning

confidence: 99%

“…In this light, we recently characterized the histone acetyltransferase (HAT) Rtt109 in P. carinii (30,31). Rtt109 HATs were first discovered in Saccharomyces cerevisiae because they catalyze a specific atypical posttranslational histone modification, i.e., histone H3 lysine 56 acetylation (H3K56ac) (32)(33)(34)(35).…”

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Pneumocystis jirovecii Rtt109, a Novel Drug Target for Pneumocystis Pneumonia in Immunosuppressed Humans

Dahlin

Kottom

Han

et al. 2014

Antimicrob Agents Chemother

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f Pneumocystis pneumonia (PcP) is a significant cause of morbidity and mortality in immunocompromised patients. In humans, PcP is caused by the opportunistic fungal species Pneumocystis jirovecii. Progress in Pneumocystis research has been hampered by a lack of viable in vitro culture methods, which limits laboratory access to human-derived organisms for drug testing. Consequently, most basic drug discovery research for P. jirovecii is performed using related surrogate organisms such as Pneumocystis carinii, which is derived from immunosuppressed rodents. While these studies provide useful insights, important questions arise about interspecies variations and the relative utility of identified anti-Pneumocystis agents against human P. jirovecii. Our recent work has identified the histone acetyltransferase (HAT) Rtt109 in P. carinii (i.e., PcRtt109) as a potential therapeutic target for PcP, since Rtt109 HATs are widely conserved in fungi but are absent in humans. To further address the potential utility of this target in human disease, we now demonstrate the presence of a functional Rtt109 orthologue in the clinically relevant fungal pathogen P. jirovecii (i.e., PjRtt109). In a fashion similar to that of Pcrtt109, Pjrtt109 restores H3K56 acetylation and genotoxic resistance in rtt109-null yeast. Recombinant PjRtt109 is an active HAT in vitro, with activity comparable to that of PcRtt109 and yeast Rtt109. PjRtt109 HAT activity is also enhanced by the histone chaperone Asf1 in vitro. PjRtt109 and PcRtt109 showed similar low micromolar sensitivities to two reported small-molecule HAT inhibitors in vitro. Together, these results demonstrate that PjRtt109 is a functional Rtt109 HAT, and they support the development of anti-Pneumocystis agents directed at Rtt109-catalyzed histone acetylation as a novel therapeutic target for human PcP.

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Rtt109‐dependent histone H3 K56 acetylation and gene activity are essential for the biological control potential of Beauveria bassiana

Cai

Wang

Shao

et al. 2018

Pest Management Science

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Pneumocystis carinii Expresses an Active Rtt109 Histone Acetyltransferase

Cited by 14 publications

References 54 publications

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

Pneumocystis jirovecii Rtt109, a Novel Drug Target for Pneumocystis Pneumonia in Immunosuppressed Humans

Rtt109‐dependent histone H3 K56 acetylation and gene activity are essential for the biological control potential of Beauveria bassiana

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