Legionella para-effectors target chromatin and promote bacterial replication

Schator, Daniel; Mondino, Sonia; Berthelet, Jérémy; Silvestre, Cristina Di; Assaya, Mathilde Ben; Rusniok, Christophe; Rodrigues‐Lima, Fernando; Wehenkel, Annemarie; Buchrieser, Carmen; Rolando, Monica

doi:10.1038/s41467-023-37885-z

Cited by 7 publications

(1 citation statement)

References 49 publications

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“…The recent discovery reported that L. pneumophila encodes an HDAC-like protein (LphD) in THP-1 cells, which synergistically collaborates with a eukaryotic methyltransferase (RomA) by specifically deacetylating H3K14 to facilitate methylation of H3K14 by RomA. Thereby fine-tuning the host cell’s gene expression and fostering bacterial intracellular replication [ 77 ]. It indicates that HDAC plays an important role in the immune evasion of L. pneumophila .…”

Section: Discussionmentioning

confidence: 99%

The role of HDAC6 in enhancing macrophage autophagy via the autophagolysosomal pathway to alleviate legionella pneumophila-induced pneumonia

Chen,

Cao,

Zheng

et al. 2024

Virulence

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Legionella pneumophila ( L. pneumophila ) is a prevalent pathogenic bacterium responsible for significant global health concerns. Nonetheless, the precise pathogenic mechanisms of L. pneumophila have still remained elusive. Autophagy, a direct cellular response to L. pneumophila infection and other pathogens, involves the recognition and degradation of these invaders in lysosomes. Histone deacetylase 6 (HDAC6), a distinctive member of the histone deacetylase family, plays a multifaceted role in autophagy regulation. This study aimed to investigate the role of HDAC6 in macrophage autophagy via the autophagolysosomal pathway, leading to alleviate L. pneumophila -induced pneumonia. The results revealed a substantial upregulation of HDAC6 expression level in murine lung tissues infected by L. pneumophila . Notably, mice lacking HDAC6 exhibited a protective response against L. pneumophila -induced pulmonary tissue inflammation, which was characterized by the reduced bacterial load and diminished release of pro-inflammatory cytokines. Transcriptomic analysis has shed light on the regulatory role of HDAC6 in L. pneumophila infection in mice, particularly through the autophagy pathway of macrophages. Validation using L. pneumophila -induced macrophages from mice with HDAC6 gene knockout demonstrated a decrease in cellular bacterial load, activation of the autophagolysosomal pathway, and enhancement of cellular autophagic flux. In summary, the findings indicated that HDAC6 knockout could lead to the upregulation of p-ULK1 expression level, promoting the autophagy-lysosomal pathway, increasing autophagic flux, and ultimately strengthening the bactericidal capacity of macrophages. This contributes to the alleviation of L. pneumophila -induced pneumonia.

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Section: Discussionmentioning

confidence: 99%

The role of HDAC6 in enhancing macrophage autophagy via the autophagolysosomal pathway to alleviate legionella pneumophila-induced pneumonia

Chen,

Cao,

Zheng

et al. 2024

Virulence

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Cross-family small GTPase ubiquitination by the intracellular pathogen Legionella pneumophila

Steinbach,

Bhadkamkar,

Jimenez-Morales

et al. 2024

MBoC

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The intracellular bacterial pathogen Legionella pneumophila ( L.p.) manipulates eukaryotic host ubiquitination machinery to form its replicative vacuole. While nearly 10% of L.p.’s ∼330 secreted effector proteins are ubiquitin ligases or deubiquitinases, a comprehensive measure of temporally resolved changes in the endogenous host ubiquitinome during infection has not been undertaken. To elucidate how L.p hijacks host cell ubiquitin signaling, we generated a proteome-wide analysis of changes in protein ubiquitination during infection. We discover that L.p. infection increases ubiquitination of host regulators of subcellular trafficking and membrane dynamics, most notably ∼40% of mammalian Ras superfamily small GTPases. We determine that these small GTPases undergo non-degradative ubiquitination at the Legionella-containing vacuole membrane. Finally, we find that the bacterial effectors SidC/SdcA play a central role in cross-family small GTPase ubiquitination, and that these effectors function upstream of SidE-family ligases in the poly-ubiquitination and retention of GTPases in the LCV membrane. This work highlights the extensive reconfiguration of host ubiquitin signaling by bacterial effectors during infection and establishes simultaneous ubiquitination of small GTPases across the Ras superfamily as a novel consequence of L.p. infection. Our findings position L.p. as a tool to better understand how small GTPases can be regulated by ubiquitination in uninfected contexts.

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Dual control of host actin polymerization by aLegionellaeffector pair

Pillon,

Michard,

Baïlo

et al. 2023

Preprint

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Host actin cytoskeleton is often targeted by pathogenic bacteria through the secretion of effectors.Legionella pneumophilavirulence relies on the injection of the largest known arsenal of bacterial proteins, over 300 Dot/Icm Type 4 Secretion System effectors, into the host cytosol. Here we define the functional interactions between VipA and LegK2, two effectors with antagonistic activities towards actin polymerization that have been proposed to interfere with the endosomal pathway. We confirmed the prominent role of LegK2 effector inLegionellainfection, as the deletion oflegK2results in defects in the inhibition of actin polymerization at theLegionellaContaining Vacuole, as well as in endosomal escape of bacteria and subsequent intracellular replication. More importantly, we observed the restoration of the ΔlegK2mutant defects, upon deletion ofvipAgene, making LegK2/VipA the first example of effector-effector suppression pair that targets the actin cytoskeleton and whose functional interaction impactsL. pneumophilavirulence. We demonstrated that LegK2 and VipA do not modulate each other's activity in a metaeffector relationship. Instead, the antagonistic activities of the LegK2/VipA effector pair would target different substrates, Arp2/3 for LegK2 and G-actin for VipA, to temporally control actin polymerization at the LCV and interfere with phagosome maturation and endosome recycling, thus contributing to the intracellular life cycle of the bacterium. Strikingly, the functional interaction between LegK2 and VipA is consolidated by an evolutionary history that has refined the best effector repertoire for the benefit ofL. pneumophilavirulence.

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Legionella para-effectors target chromatin and promote bacterial replication

Cited by 7 publications

References 49 publications

The role of HDAC6 in enhancing macrophage autophagy via the autophagolysosomal pathway to alleviate legionella pneumophila-induced pneumonia

The role of HDAC6 in enhancing macrophage autophagy via the autophagolysosomal pathway to alleviate legionella pneumophila-induced pneumonia

Cross-family small GTPase ubiquitination by the intracellular pathogen Legionella pneumophila

Dual control of host actin polymerization by aLegionellaeffector pair

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