Legionella Manipulates Non-canonical SNARE Pairing Using a Bacterial Deubiquitinase

Kitao, Tomoe; Taguchi, Kyoichiro; Seto, Shintaro; Arasaki, Kohei; Ando, Hiromitsu; Nagai, Hiroki; Kubori, Tomoko

doi:10.1016/j.celrep.2020.108107

Cited by 21 publications

(26 citation statements)

References 75 publications

(100 reference statements)

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“…The SNARE protein Sec22b involved in membrane fusion is a substrate of LotB; this protein is ubiquitinated in cells infected with L. pneumophila and LotB appears to function to counteract such modification ( Shin et al, 2020a ). The removal of ubiquitin from Sec22b abolishes the interaction between Sec22b on the LCV and the t-SNARE syntaxin 3, resulting in the dissociation of the latter from the bacterial phagosome ( Kitao et al, 2020b ). Interestingly, ubiquitination and recruitment of Rab10 to the LCV by SidC and SdcA are regulated by a third OUT-like Dub Lem27 (Lpg2529) (also known as LotC) coded for by L. pneumophila ( Schubert et al, 2020 ; Shin et al, 2020a ).…”

Section: Dubsmentioning

confidence: 99%

Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

et al. 2021

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Ubiquitination is a commonly used post-translational modification (PTM) in eukaryotic cells, which regulates a wide variety of cellular processes, such as differentiation, apoptosis, cell cycle, and immunity. Because of its essential role in immunity, the ubiquitin network is a common target of infectious agents, which have evolved various effective strategies to hijack and co-opt ubiquitin signaling for their benefit. The intracellular pathogen Legionella pneumophila represents one such example; it utilizes a large cohort of virulence factors called effectors to modulate diverse cellular processes, resulting in the formation a compartment called the Legionella-containing vacuole (LCV) that supports its replication. Many of these effectors function to re-orchestrate ubiquitin signaling with distinct biochemical activities. In this review, we highlight recent progress in the mechanism of action of L. pneumophila effectors involved in ubiquitination and discuss their roles in bacterial virulence and host cell biology.

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Section: Dubsmentioning

confidence: 99%

Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

et al. 2021

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“…The functional role and protein targets of LotA during infection of host cells is currently unknown, and like many of the L. pneumophila effectors that manipulate the eukaryotic ubiquitination system, analysis of the role of LotA during infection of the natural amoebae host will be crucial to unravel the exact function of this effector. Another effector, LotB (Lpg1621/Ceg23), also harbors an OTU domain and deubiquitinates K 63 linked polyubiquitin chains at the LCV (Figure 3B) [111,112]. Unlike LotA, LotB has a clear host target resulting in modulation of the early secretory pathway [112].…”

Section: Deubiquitinasesmentioning

confidence: 99%

“…Another effector, LotB (Lpg1621/Ceg23), also harbors an OTU domain and deubiquitinates K 63 linked polyubiquitin chains at the LCV (Figure 3B) [111,112]. Unlike LotA, LotB has a clear host target resulting in modulation of the early secretory pathway [112]. Membrane fusion in eukaryotes requires the pairing of proteins called soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) [113].…”

Section: Deubiquitinasesmentioning

confidence: 99%

“…The host vesicular SNARE, Sec22B is recruited to the LCV and binds to the t-SNARE, Stx3 to help establish the early LCV membrane [114][115][116]. At the LCV, Sec22b is ubiquitinated with K 63 -linked polyubiquitinated chains and this is dependent on effector translocation by L. pneumophila [112]. LotB specifically deubiquitinates the K 63 -linked polyubiquitinated chains from Sec22b at the LCV, resulting in disassociation of Stx3 from Sec22b (Figure 3B) [112].…”

Section: Deubiquitinasesmentioning

confidence: 99%

“…At the LCV, Sec22b is ubiquitinated with K 63 -linked polyubiquitinated chains and this is dependent on effector translocation by L. pneumophila [112]. LotB specifically deubiquitinates the K 63 -linked polyubiquitinated chains from Sec22b at the LCV, resulting in disassociation of Stx3 from Sec22b (Figure 3B) [112]. Even though LotB has a clear host cell target, the overall functional consequence of its activity, at least in mammalian cells is unclear, since deletion of the lotB gene does not impair intracellular replication of L. pneumophila and formation of the LCV [112].…”

Section: Deubiquitinasesmentioning

confidence: 99%

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Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts

Price

Kwaik

2021

Biomolecules

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The ubiquitin pathway is highly conserved across the eukaryotic domain of life and plays an essential role in a plethora of cellular processes. It is not surprising that many intracellular bacterial pathogens often target the essential host ubiquitin pathway. The intracellular bacterial pathogen Legionella pneumophila injects into the host cell cytosol multiple classes of classical and novel ubiquitin-modifying enzymes that modulate diverse ubiquitin-related processes in the host cell. Most of these pathogen-injected proteins, designated as effectors, mimic known E3-ubiquitin ligases through harboring F-box or U-box domains. The classical F-box effector, AnkB targets host proteins for K48-linked polyubiquitination, which leads to excessive proteasomal degradation that is required to generate adequate supplies of amino acids for metabolism of the pathogen. In contrast, the SidC and SdcA effectors share no structural similarity to known eukaryotic ligases despite having E3-ubiquitin ligase activity, suggesting that the number of E3-ligases in eukaryotes is under-represented. L. pneumophila also injects into the host many novel ubiquitin-modifying enzymes, which are the SidE family of effectors that catalyze phosphoribosyl-ubiquitination of serine residue of target proteins, independently of the canonical E1-2-3 enzymatic cascade. Interestingly, the environmental bacterium, L. pneumophila, has evolved within a diverse range of amoebal species, which serve as the natural hosts, while accidental transmission through contaminated aerosols can cause pneumonia in humans. Therefore, it is likely that the novel ubiquitin-modifying enzymes of L. pneumophila were acquired by the pathogen through interkingdom gene transfer from the diverse natural amoebal hosts. Furthermore, conservation of the ubiquitin pathway across eukaryotes has enabled these novel ubiquitin-modifying enzymes to function similarly in mammalian cells. Studies on the biological functions of these effectors are likely to reveal further novel ubiquitin biology and shed further lights on the evolution of ubiquitin.

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Legionella effectors SidC/SdcA ubiquitinate multiple small GTPases and SNARE proteins to promote phagosomal maturation

Ma,

Shu,

Liu

et al. 2024

Cell. Mol. Life Sci.

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Protein ubiquitination is one of the most important posttranslational modifications (PTMs) in eukaryotes and is involved in the regulation of almost all cellular signaling pathways. The intracellular bacterial pathogen Legionella pneumophila translocates at least 26 effectors to hijack host ubiquitination signaling via distinct mechanisms. Among these effectors, SidC/SdcA are novel E3 ubiquitin ligases with the adoption of a Cys-His-Asp catalytic triad. SidC/SdcA are critical for the recruitment of endoplasmic reticulum (ER)-derived vesicles to the Legionella-containing vacuole (LCV). However, the ubiquitination targets of SidC/SdcA are largely unknown, which restricts our understanding of the mechanisms used by these effectors to hijack the vesicle trafficking pathway. Here, we demonstrated that multiple Rab small GTPases and target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins are bona fide ubiquitination substrates of SidC/SdcA. SidC/SdcA-mediated ubiquitination of syntaxin 3 and syntaxin 4 promotes their unconventional pairing with the vesicle-SNARE protein Sec22b, thereby contributing to the membrane fusion of ER-derived vesicles with the phagosome. In addition, our data reveal that ubiquitination of Rab7 by SidC/SdcA is critical for its association with the LCV membrane. Rab7 ubiquitination could impair its binding with the downstream effector Rab-interacting lysosomal protein (RILP), which partially explains why LCVs avoid fusion with lysosomes despite the acquisition of Rab7. Taken together, our study reveals the biological mechanisms employed by SidC/SdcA to promote the maturation of the LCVs.

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Legionella Manipulates Non-canonical SNARE Pairing Using a Bacterial Deubiquitinase

Cited by 21 publications

References 75 publications

Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts

Legionella effectors SidC/SdcA ubiquitinate multiple small GTPases and SNARE proteins to promote phagosomal maturation

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