The structure of <i>Legionella</i> effector protein LpnE provides insights into its interaction with Oculocerebrorenal syndrome of Lowe (<scp>OCRL</scp>) protein

Voth, Kevin; Chung, Ivy Yeuk Wah; Straaten, K. van; Li, L.; Boniecki, Michal T.; Cygler, Mirosław

doi:10.1111/febs.14710

Cited by 9 publications

(14 citation statements)

References 41 publications

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“…In Legionella spp., the RCC1 repeat effectors localise to the pathogen vacuole or the host plasma membrane and target distinct components of the Ran GTPase cycle, including Ran modulators and the small GTPase itself (Swart et al, 2020). Another example is the Sel-1 repeat which may have a role in localisation to Cis-Golgi (Voth et al, 2019).…”

Section: Exploitation Of Tandem Repeat Containing Domainsmentioning

confidence: 99%

The evolution and role of eukaryotic-like domains in environmental intracellular bacteria: the battle with a eukaryotic cell

Martyn

Gómez-Valero

Buchrieser

2022

FEMS Microbiology Reviews

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Intracellular pathogens that are able to thrive in different environments, such as Legionella spp. which preferentially live in protozoa in aquatic environments or environmental Chlamydiae which replicate either within protozoa or a range of animals, possess a plethora of cellular biology tools to influence their eukaryotic host. The host manipulation tools that evolved in the interaction with protozoa, confer these bacteria the capacity to also infect phylogenetically distinct eukaryotic cells, such as macrophages and thus they can also be human pathogens. To manipulate the host cell, bacteria use protein secretion systems and molecular effectors. Although these molecular effectors are encoded in bacteria, they are expressed and function in a eukaryotic context often mimicking or inhibiting eukaryotic proteins. Indeed, many of these effectors have eukaryotic-like domains. In this review we propose that the main pathways environmental intracellular bacteria need to subvert in order to establish the host eukaryotic cell as a replication niche are chromatin remodelling, ubiquitination signalling, and modulation of protein-protein interactions via tandem repeat domains. We then provide mechanistic insight into how these proteins might have evolved as molecular weapons. Finally, we highlight that in environmental intracellular bacteria the number of eukaryotic-like domains and proteins is considerably higher than in intracellular bacteria specialised to an isolated niche, such as obligate intracellular human pathogens. As mimics of eukaryotic proteins are critical components of host pathogen interactions, this distribution of eukaryotic-like domains suggests that the environment has selected them.

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Section: Exploitation Of Tandem Repeat Containing Domainsmentioning

confidence: 99%

The evolution and role of eukaryotic-like domains in environmental intracellular bacteria: the battle with a eukaryotic cell

Martyn

Gómez-Valero

Buchrieser

2022

FEMS Microbiology Reviews

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“…This construct terminates just after the final hydrophilic helical stretch and excludes the following loop and TM region. The MavE(2-172) insert DNA sequence was placed into pMCSG7 and pRL652 vectors by ligation-independent cloning (LIC), incorporating an N-terminal tobacco etch virus (TEV)-cleavable His6 or glutathione S-transferase (GST) tag, respectively (106,107). His6-MavE (2-172) expressed poorly in BL21(DE3) pLysS (Promega) and GST-MavE (2-172) did not readily bind the glutathione resin.…”

Section: Methodsmentioning

confidence: 99%

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Vaughn

Voth

Price

et al. 2021

mBio

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Diversion of the Legionella pneumophila-containing vacuole (LCV) from the host endosomal-lysosomal degradation pathway is one of the main virulence features essential for manifestation of Legionnaires’ pneumonia. Many of the ∼350 Dot/Icm-injected effectors identified in L. pneumophila have been shown to interfere with various host pathways and processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. While most single effector mutants of L. pneumophila do not exhibit a defective phenotype within macrophages, we show that the MavE effector is essential for intracellular growth of L. pneumophila in human monocyte-derived macrophages (hMDMs) and amoebae and for intrapulmonary proliferation in mice. The mavE null mutant fails to remodel the LCV with endoplasmic reticulum (ER)-derived vesicles and is trafficked to the lysosomes where it is degraded, similar to formalin-killed bacteria. During infection of hMDMs, the MavE effector localizes to the poles of the LCV membrane. The crystal structure of MavE, resolved to 1.8 Å, reveals a C-terminal transmembrane helix, three copies of tyrosine-based sorting motifs, and an NPxY eukaryotic motif, which binds phosphotyrosine-binding domains present on signaling and adaptor eukaryotic proteins. Two point mutations within the NPxY motif result in attenuation of L. pneumophila in both hMDMs and amoeba. The substitution defects of P78 and D64 are associated with failure of vacuoles harboring the mutant to be remodeled by the ER and results in fusion of the vacuole to the lysosomes leading to bacterial degradation. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion. IMPORTANCE Intracellular proliferation of Legionella pneumophila within a vacuole in human alveolar macrophages is essential for manifestation of Legionnaires’ pneumonia. Intravacuolar growth of the pathogen is totally dependent on remodeling the L. pneumophila-containing vacuole (LCV) by the ER and on its evasion of the endosomal-lysosomal degradation pathway. The pathogen has evolved to inject ∼350 protein effectors into the host cell where they modulate various host processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. We show that the MavE effector localizes to the poles of the LCV membrane and is essential for lysosomal evasion and intracellular growth of L. pneumophila and for intrapulmonary proliferation in mice. The crystal structure of MavE shows an NPxY eukaryotic motif essential for ER-mediated remodeling and lysosomal evasion by the LCV. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion.

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“…Sequences of wild-type COA7 were submitted to the Swiss-Model server 3 for modeling in automated mode on template 6deh (LpnE). The crystal structure of the Legionella effector protein LpnE(73–375) was solved to 1.75Å resolution ( Voth et al, 2019 ). Both proteins belong to the SEL1-like repeat family with e-value at 9.7e-69 and 3.7e-15 for LpnE and COA7, respectively 4 and can be evolutionary linked by Pfam HMM and phylogenetic tree mapping ( Schreiber et al, 2014 ; Mistry et al, 2021 ).…”

Section: Patient and Methodsmentioning

confidence: 99%

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

et al. 2021

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ObjectiveThe cytochrome c oxidase assembly factor 7 (COA7) gene encodes a protein localized to mitochondria that is involved in the assembly of mitochondrial respiratory chain complex IV. Here, we report the clinical, genetic and biochemical analysis of a female patient with suspected mitochondrial disorder and novel variants in COA7, that presented with a considerably different phenotype and age of onset than the five COA7 patients reported to date.MethodsWe performed trio-exome sequencing in the affected patient and both parents. To verify the pathogenicity of the detected variants in COA7, mitochondrial enzyme activities and oxygen consumption rate were investigated in fibroblasts of the patient and her parents.ResultsA Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age. In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities. Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser). Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts.InterpretationHitherto, characteristic features of COA7 patients were described as slowly progressing neuropathy and spinocerebellar ataxia, starting at the toddler age and progressing into adulthood. In contrast, our patient was reported to show developmental delay from 3 months of age, which was found to be due to a rapidly progressive encephalopathy and brain atrophy seen at 9 months of age. Unexpectedly, the genetic investigation revealed a COA7-associated mitochondrial disease, which was confirmed functionally. Thus, this report broadens the genetic and clinical spectrum of this heterogeneous mitochondriopathy and highlights the value of the presented unbiased approach.

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The structure of Legionella effector protein LpnE provides insights into its interaction with Oculocerebrorenal syndrome of Lowe (OCRL) protein

Cited by 9 publications

References 41 publications

The evolution and role of eukaryotic-like domains in environmental intracellular bacteria: the battle with a eukaryotic cell

The evolution and role of eukaryotic-like domains in environmental intracellular bacteria: the battle with a eukaryotic cell

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

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