Methylomic Changes of Autophagy-Related Genes by Legionella Effector Lpg2936 in Infected Macrophages

Maksoud, Ahmed I. Abd El; Elebeedy, Dalia; Abass, Nasser; Awad, Ahmed M.; Nasr, Ghada M.; Roshdy, Tamer; Khalil, Hany

doi:10.3389/fcell.2019.00390

Cited by 24 publications

(26 citation statements)

References 47 publications

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“…Beclin1 and ATG14L synergistically facilitate the formation of autophagosomal membrane that is related to ATG5 and ATG12 [ 10 ]. Under the catalysis of E1-like enzyme ATG7 and E2-like enzyme ATG10, the formed ATG5/ATG12/ATG16(L) complex facilitates the recruitment and conversion of microtubuleassociated protein light chain 3 (LC3-I) to the membrane-bound LC3-II form [ 11 ]. LC3-II also binds to the adaptor protein p62/sequestosome1 (SQSTM1) to degrade the ubiquitinated protein aggregates in autophagolysosome [ 12 ], and thus recycling amino acids and other metabolic building blocks to maintain cellular homeostasis.…”

Section: Mechanisms Of Autophagymentioning

confidence: 99%

Targeting autophagy to overcome drug resistance: further developments

2020

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Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.

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Section: Mechanisms Of Autophagymentioning

confidence: 99%

Targeting autophagy to overcome drug resistance: further developments

2020

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“…The L. pneumophila effector Lpg2936 has recently been implicated as a regulator of autophagosome formation (Abd El Thomas et al Maksoud et al, 2019). This finding arose from the observation that during L. pneumophila infection, the expression of autophagy-related genes ATG7 and LC3B was reduced, alongside a decrease in the expression of unlipidated LC3-I, lipidated LC3-II, and the ATG5-ATG12-ATG16L1 protein complex.…”

Section: Lpg2936-epigenetic Modulator Of Autophagy Componentsmentioning

confidence: 99%

“…This finding arose from the observation that during L. pneumophila infection, the expression of autophagy-related genes ATG7 and LC3B was reduced, alongside a decrease in the expression of unlipidated LC3-I, lipidated LC3-II, and the ATG5-ATG12-ATG16L1 protein complex. Using RNAi against Lpg2936, investigators were able to restore expression of these autophagy-related genes during L. pneumophila infection and consequently inhibited bacterial replication (Abd El Maksoud et al, 2019). Bioinformatic and structural analysis previously established that Lpg2936 is a ribosomal RNA protein similar to RsmE-like methyltransferases (Pinotsis and Waksman, 2017).…”

Section: Lpg2936-epigenetic Modulator Of Autophagy Componentsmentioning

confidence: 99%

“…Bioinformatic and structural analysis previously established that Lpg2936 is a ribosomal RNA protein similar to RsmE-like methyltransferases (Pinotsis and Waksman, 2017). Subsequent examinations demonstrated that Lpg2936 is translocated into the host nucleus where it recognizes the GATC motif in the promoter regions of ATG7 and LC3B and induces irreversible methyladenine changes in this motif from GATC to G(6 mA)TC (Abd El Maksoud et al, 2019). Similar to RNAi against Lpg2936, methylation inhibitors reduced L. pneumophila replication and restored expression of autophagy-related genes (Abd El Maksoud et al, 2019).…”

Section: Lpg2936-epigenetic Modulator Of Autophagy Componentsmentioning

confidence: 99%

“…Subsequent examinations demonstrated that Lpg2936 is translocated into the host nucleus where it recognizes the GATC motif in the promoter regions of ATG7 and LC3B and induces irreversible methyladenine changes in this motif from GATC to G(6 mA)TC (Abd El Maksoud et al, 2019). Similar to RNAi against Lpg2936, methylation inhibitors reduced L. pneumophila replication and restored expression of autophagy-related genes (Abd El Maksoud et al, 2019). Collectively, this data suggests that Lpg2936 is a transcription factor that translocates into the host cells to regulate autophagosome formation through epigenetic modification of ATG7 and LC3 promoter regions thereby enhancing bacterial replication (Figure 4).…”

Section: Lpg2936-epigenetic Modulator Of Autophagy Componentsmentioning

confidence: 99%

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Interfering with Autophagy: The Opposing Strategies Deployed by Legionella pneumophila and Coxiella burnetii Effector Proteins

Thomas

Newton

Lau

et al. 2020

Front. Cell. Infect. Microbiol.

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Autophagy is a fundamental and highly conserved eukaryotic process, responsible for maintaining cellular homeostasis and releasing nutrients during times of starvation. An increasingly important function of autophagy is its role in the cell autonomous immune response; a process known as xenophagy. Intracellular pathogens are engulfed by autophagosomes and targeted to lysosomes to eliminate the threat to the host cell. To counteract this, many intracellular bacterial pathogens have developed unique approaches to overcome, evade, or co-opt host autophagy to facilitate a successful infection. The intracellular bacteria Legionella pneumophila and Coxiella burnetii are able to avoid destruction by the cell, causing Legionnaires' disease and Q fever, respectively. Despite being related and employing homologous Dot/Icm type 4 secretion systems (T4SS) to translocate effector proteins into the host cell, these pathogens have developed their own unique intracellular niches. L. pneumophila evades the host endocytic pathway and instead forms an ER-derived vacuole, while C. burnetii requires delivery to mature, acidified endosomes which it remodels into a large, replicative vacuole. Throughout infection, L. pneumophila effectors act at multiple points to inhibit recognition by xenophagy receptors and disrupt host autophagy, ensuring it avoids fusion with destructive lysosomes. In contrast, C. burnetii employs its effector cohort to control autophagy, hypothesized to facilitate the delivery of nutrients and membrane to support the growing vacuole and replicating bacteria. In this review we explore the effector proteins that these two organisms utilize to modulate the host autophagy pathway in order to survive and replicate. By better understanding how these pathogens manipulate this highly conserved pathway, we can not only develop better treatments for these important human diseases, but also better understand and control autophagy in the context of human health and disease.

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Characterization and Expression Analysis of Extradiol and Intradiol Dioxygenase of Phenol-Degrading Haloalkaliphilic Bacterial Isolates

et al. 2022

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Haloalkophilic bacteria have a potential advantage as a bioremediation organism of high oil-polluted and industrial wastewater. In the current study, Haloalkaliphilic isolates were obtained from Hamralake, Wadi EL-Natrun, Egypt. The phenotype script, biochemical characters, and sequence analysis of bacterial-16S rRNA were used to identify the bacterial isolates; Halomonas HA1 and Marinobacter HA2. These strains required high concentrations of NaCl to ensure bacterial growth, especially Halomonas HA1 strain. Notably, both isolates can degrade phenol at optimal pH values, between 8 and 9, with the ability to grow in pH levels up to 11, like what was seen in the Halomonas HA1 strain. Moreover, both isolates represent two different mechanistic pathways for phenol degradation. Halomonas HA1 exploits the 1,2 phenol meta-cleavage pathway, while Marinobacter HA2 uses the 2,3 ortho-cleavage pathway as indicated by universal primers for 1,2 and 2,3 CTD genes. Interestingly, Marinobacter HA2 isolate eliminated the added phenol within an incubation period of 72 h, while the Halomonas HA1 isolate invested 96 h in degrading 84% of the same amount of phenol. Phylogenetic analysis of these 1,2 CTD (catechol dioxygenase) sequences clearly showed an evolutionary relationship between 1,2 dioxygenases of both Halomonadaceae and Pseudomonadaceae. In comparison, 2,3 CTD of Marinobacter HA2 shared the main domains of the closely related species. Furthermore, semi-quantitative RT-PCR analysis proved the constitutive expression pattern of both dioxygenase genes. These findings provide new isolates of Halomonas sp. and Marinobacter sp. that can degrade phenol at high salt and pH conditions via two independent mechanisms.

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Methylomic Changes of Autophagy-Related Genes by Legionella Effector Lpg2936 in Infected Macrophages

Cited by 24 publications

References 47 publications

Targeting autophagy to overcome drug resistance: further developments

Targeting autophagy to overcome drug resistance: further developments

Interfering with Autophagy: The Opposing Strategies Deployed by Legionella pneumophila and Coxiella burnetii Effector Proteins

Characterization and Expression Analysis of Extradiol and Intradiol Dioxygenase of Phenol-Degrading Haloalkaliphilic Bacterial Isolates

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