The unity of opposites: Strategic interplay between bacterial effectors to regulate cellular homeostasis

Iyer, Shalini; Das, Chittaranjan

doi:10.1016/j.jbc.2021.101340

Cited by 14 publications

(10 citation statements)

References 168 publications

(290 reference statements)

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“…The number of bacterial toxins discovered to specifically direct their activity toward altering Rab biology is on the rise. SidM (also known as DrrA), LepB, and Lgp0393 of Legionella pneumophila, SopE, SopE2, and SopD2 of Salmonella enterica, EspG of Enteropathogenic Escherichia coli, and VirA of Shigella flexneri mimic host regulators that alter the Rab activation state [36][37][38][39][40][41][42][43][44][45][46][47][48][49] In this study, we show unlike any other effectors that target Rabs, MCF is delivered from a toxin expressed by an extracellular bacterium to cleave and degrade a broad range of Rab GTPases, which ultimately results in fragmentation of the Golgi and mitochondrial damage (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…Other effectors covalently modify Rabs through AMPylation (L. pneumophila SidM), Pseudomonas aeruginosa ExoS), and ubiquitination (L. pneumophila SidE, SdeA, SdeB, and SdeC). All of these covalent modification prevent nucleotide exchange or interaction with GAPs, GEFs, or Rab effectors39,44,45,47,[50][51][52][53][54][55][56][57][58][59][60] . However, only the Type III secretion effector GtgE of S. enterica has been found to directly cleave Rabs to date48,[61][62][63] .…”

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confidence: 99%

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VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

Herrera¹,

Packer²,

Rosas‐Lemus

et al. 2023

Preprint

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Vibrio vulnificuscauses life threatening infections dependent upon the effectors released from the Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The Makes Caterpillars Floppy-like (MCF) cysteine protease effector is activated by host ADP ribosylation factors (ARFs), although the targets of processing activity were unknown. In this study we show MCF binds Ras-related proteins in brain (Rab) GTPases at the same interface occupied by ARFs and then cleaves and/or degrades 24 distinct members of the Rab GTPases family. The cleavage occurs in the C-terminal tails of Rabs. We determine the crystal structure of MCF as a swapped dimer revealing the open, activated state of MCF and then use structure prediction algorithms to show that structural composition, rather than sequence or localization, determine Rabs selected as MCF proteolytic targets. Once cleaved, Rabs become dispersed in cells to drive organelle damage and cell death to promote pathogenesis of these rapidly fatal infections.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

Herrera¹,

Packer²,

Rosas‐Lemus

et al. 2023

Preprint

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“…Balanced modulation of host processes has recently emerged as a prominent feature associated with the interactions between L. pneumophila and its hosts. In some cases, the balance is achieved by effector pairs with opposite biochemical activity which may function at different phases of infection [52]. In other cases, the importance of balance lies in the cellular locations of the molecular events regulated by the effectors [17].…”

Section: Discussionmentioning

confidence: 99%

Legionella pneumophilamodulates host cytoskeleton by an effector of transglutaminase activity

Liu

Luo

2022

Preprint

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The bacterial pathogen Legionella pneumophila delivers more than 330 effector proteins into host cells through its Dot/Icm type IV secretion system (T4SS) to facilitate its intracellular replication. A number of these effectors modulate organelle trafficking pathways to create a membrane-bound niche called the Legionella containing vacuole (LCV). In this study, we found that L. pneumophila induces F-actin accumulation in host cell cortex by its Dot/Icm substrate RavJ (Lpg0944). RavJ harbors an C101H138D170 motif associated with human tissue transglutaminases (TGs). We showed that RavJ catalyzes a covalent linkage between actin and the Motin family proteins Angiomotin (AMOT) and Angiomotin-like 1 (AMOTL1), proteins known to regulate tube formation and cell migration. Further study revealed that RavJ-induced crosslink between actin and AMOT occurs on its Gln354 residue. Crosslink between actin and AMOT significantly reduces the binding between actin and its binding partner cofilin, suggesting that RavJ inhibits actin depolymerization. We also demonstrated that the metaeffector LegL1 directly interacts with RavJ to antagonize its transglutaminase activity, leading to reduced crosslink between actin and Motin proteins. Our results reveal a novel mechanism of modulating the host actin cytoskeleton by L. pneumophila.

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“…Both post-translational modifications can subsequently be reversed by the antagonistic effectors SidD and Lem3, respectively [105][106][107]. A growing list of similar antagonistic effector relationships highlights how the effector arsenal equips the bacteria to exert exact temporal and spatial control of host protein activity (reviewed in [108]). Moreover, the observation that co-expression but not individual expression of the effectors SidP and Lem14 inhibits yeast growth indicates that synergistic interactions also exist [109].…”

Section: General Concepts and Functional Featuresmentioning

confidence: 99%

The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

et al. 2022

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To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at the host–pathogen interface and/or deliver them directly into host cells. An outstanding example of the complexity and sophistication of secretion systems and the diversity of their protein substrates, effectors, is the Defective in organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB secretion system (T4BSS) of Legionella pneumophila and related species. Legionella species are facultative intracellular pathogens of environmental protozoa and opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number of effectors, more than 300 per L. pneumophila strain, and is essential for evasion of phagolysosomal degradation and exploitation of protozoa and human macrophages as replicative niches. Recent technological advancements in the imaging of large protein complexes have provided new insight into the architecture of the T4BSS and allowed us to propose models for the transport mechanism. At the same time, significant progress has been made in assigning functions to about a third of L. pneumophila effectors, discovering unprecedented new enzymatic activities and concepts of host subversion. In this review, we describe the current knowledge of the workings of the Dot/Icm T4BSS machinery and provide an overview of the activities and functions of the to-date characterized effectors in the interaction of L. pneumophila with host cells.

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The unity of opposites: Strategic interplay between bacterial effectors to regulate cellular homeostasis

Cited by 14 publications

References 168 publications

VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

Legionella pneumophilamodulates host cytoskeleton by an effector of transglutaminase activity

The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

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