Viral manipulation of cell polarity signalling

Javorsky, Airah; Humbert, Patrick O.; Kvansakul, Marc

doi:10.1016/j.bbamcr.2023.119536

Cited by 3 publications

(1 citation statement)

References 204 publications

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“…To our knowledge, SseM is unique among Salmonella effectors in containing a functional PBM and as a bacterial protein targeting the DAPC. Several viral oncoproteins target DLG1 to regulate viral virulence ( 41 , 42 ). It is, therefore, now essential to investigate the biochemical consequences and physiological significance of SseM’s interaction with DLG1 and DAPC components.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Yu,

Xie,

et al. 2024

mBio

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The injectisome encoded by Salmonella pathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterize the secretome of a clinical strain of invasive non-typhoidal Salmonella enterica serovar Enteritidis that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein. sseM is widely distributed among the five subspecies of Salmonella enterica, is found in many clinically relevant serovars, and is co-transcribed with pipB2 , a SPI-2 effector gene. The translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely, β-2-syntrophin, utrophin/dystrophin, α-catulin, α-dystrobrevin, and β-dystrobrevin. The interaction between SseM and β-2-syntrophin and α-dystrobrevin was verified in Salmonella Typhimurium-infected cells and relied on the postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain of β-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A Δ sseM mutant strain had a small competitive advantage over the wild-type strain in the S . Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild-type SseM from S . Typhimurium or S . Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within a Salmonella effector mediates interactions with the DAPC and modulates the systemic growth of bacteria in mice. Furthermore, the Δ sseM mutant strain displayed enhanced replication in bone marrow-derived macrophages, demonstrating that SseM restrains intracellular bacterial growth to modulate Salmonella virulence. IMPORTANCE In Salmonella enterica , the injectisome machinery encoded by Salmonella pathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells, which are required for Salmonella virulence. The identification and functional characterization of SPI-2 injectisome effectors advance our understanding of the interplay between Salmonella and its host(s). Using an optimized method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal Salmonella enterica serovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector—SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif that is essential for interaction with the PDZ-containing host protein β-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique among Salmonella effectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

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Section: Discussionmentioning

confidence: 99%

Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Yu,

Xie,

et al. 2024

mBio

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Modulation ofSalmonellavirulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Yu,

Xie,

et al. 2023

Preprint

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The injectisome encoded bySalmonellapathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterise the secretome of a clinical strain of invasive non-typhoidalSalmonella entericaserovar Enteritidis, that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein.sseMis widely distributed between the five subspecies ofSalmonella enterica,is found in many clinically-relevant serovars, and is co-transcribed withpipB2, aSPI-2 effector gene. Translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely β-2-syntrophin, utrophin/ dystrophin, α-catulin, α-dystrobrevin and β-dystrobrevin. The interaction between SseM and β-2-syntrophin and α-dystrobrevin was verified inS.Typhimurium-infected cells and relied on the PDZ domain of β-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseMmutant strain had a small competitive advantage over the wild-type strain in theS.Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild type SseM fromS.Typhimurium orS.Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within aSalmonellaeffector mediates interactions with the DAPC and modulates systemic growth of bacteria in mice.ImportanceInSalmonella enterica, the injectisome machinery encoded bySalmonellapathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells that are required forSalmonellavirulence. The identification and functional characterisation of SPI-2 injectisome effectors advances our understanding of the interplay betweenSalmonellaand its host(s). Using an optimised method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal (iNTS)Salmonella entericaserovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector - SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a PDZ-binding motif that is essential for interaction with the PDZ-containing host protein β-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique amongSalmonellaeffectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

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Bloodmeals fuel dengue virus replication in the female mosquito Aedes aegypti

Huang,

Lee,

Shiao

et al. 2024

J Virol

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Vector competence defines the ability of a vector to acquire, host, and transmit a pathogen. Understanding the molecular determinants of the mosquitos’ competence to host dengue virus (DENV) holds promise to prevent its transmission. To this end, we employed RNA-seq to profile mRNA transcripts of the female Aedes aegypti mosquitos feeding on naïve vs viremic mouse. While most transcripts (12,634) did not change their abundances, 360 transcripts showed decreases. Biological pathway analysis revealed representatives of the decreased transcripts involved in the wnt signaling pathway and hippo signaling pathway. One thousand three hundred fourteen transcripts showed increases in abundance and participate in 21 biological pathways including amino acid metabolism, carbon metabolism, fatty acid metabolism, and oxidative phosphorylation. Inhibition of oxidative phosphorylation with antimycin A reduced oxidative phosphorylation activity and ATP concentration associated with reduced DENV replication in the Aedes aegypti cells. Antimycin A did not affect the amounts of the non-structural proteins 3 and 5, two major components of the replication complex. Ribavirin, an agent that reduces GTP concentration, recapitulated the effects of reduced ATP concentration on DENV replication. Knocking down one of the oxidative phosphorylation components, ATP synthase subunit β, reduced DENV replication in the mosquitos. In summary, our results suggest that DENV enhances metabolic pathways in the female Aedes aegypti mosquitos to supply nutrients and energy for virus replication. ATP synthase subunit β knockdown might be exploited to reduce the mosquitos’ competence to host and transmit DENV. IMPORTANCE Through evolution, the mosquito-borne viruses have adapted to the blood-feeding behaviors of their opportunist hosts to fulfill a complete lifecycle in humans and mosquitos. Disruption in the mosquitos’ ability to host these viruses offers strategies to prevent diseases caused by them. With the advent of genomic tools, we discovered that dengue virus (DENV) benefited from the female mosquitos’ bloodmeals for metabolic and energetic supplies for replication. Chemical or genetic disruption in these supplies reduced DENV replication in the female mosquitos. Our discovery can be exploited to produce genetically modified mosquitos, in which DENV infection leads to disruption in the supplies and thereby reduces replication and transmission. Our discovery might be extrapolated to prevent mosquito-borne virus transmission and the diseases they cause.

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Viral manipulation of cell polarity signalling

Cited by 3 publications

References 204 publications

Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Modulation ofSalmonellavirulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex

Bloodmeals fuel dengue virus replication in the female mosquito Aedes aegypti

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