A
            <i>Legionella</i>
            type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors

Ge, Jianning; Xu, Hao; Li, Ting; Zhou, Yan; Zhang, Zhibin; Li, Shan; Liu, Liping; Shao, Feng

doi:10.1073/pnas.0907200106

Cited by 149 publications

(177 citation statements)

References 34 publications

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“…A second facet of innate immunity that controls cytokine transcription and is triggered by L. pneumophila infection in murine and human cells is signaling through NF-B (32,33,(35)(36)(37)(38)(39). Thus, we assessed levels of I B␣, the inhibitor of NF-B that keeps the transcription factor sequestered in the cytoplasm of the cell.…”

Section: Resultsmentioning

confidence: 99%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-B) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)-or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.KEYWORDS Legionella pneumophila, TLR2, cytokine, innate immunity, macrophage, type II secretion L egionella pneumophila, a Gram-negative bacterium that is widespread in aquatic habitats, is the principal agent of Legionnaires' disease pneumonia (1-6). In the lungs, Legionella bacteria invade and grow in resident macrophages and then trigger severe inflammation (2). In macrophages, L. pneumophila evades the degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (7,8). Two protein secretion systems, Lsp type II secretion (T2S) and Dot/Icm type IV secretion (T4S), play major roles in the pathogenesis of L. pneumophila (9, 10). In T2S, protein substrates are first translocated across the inner membrane, and upon the action of the T2S pilus-like apparatus, they then exit the bacterial cell through a specific outer membrane pore (11). Using proteomics and enzymatic assays, we have shown that the T2S system of L. pneumo-

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Section: Resultsmentioning

confidence: 99%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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“…We believe that TAK1 phosphorylation is outcompeted by secreted Legionella factors, as evidenced by the observed reduction of TAK1 driven phosphorylation of Rab1 exposed to GEF DrrA and the rescue of pT75 Rab1 levels in ΔankX,drrA-infected cells. Interestingly, Legionella also stimulate NF-κB, p38, and JNK signaling through TLR-independent mechanisms during infection (49,50). TAK1 normally serves to respond to TLR signaling and activate these same pathways during infection.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPaseactivating protein (GAP) enzymes, and is exclusive to membranelocalized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

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“…Precisely how the H. pylori LPS stimulates non-canonical NF-κB signaling is unknown, although this action requires NIK and IKKα [103]. Another bacterial pathogen known to stimulate both the canonical and non-canonical NF-κB pathways is Legionella pneumophila, a pathogen that infects alveolar lung macrophages and causes Legionnaire's disease [106]. In contrast to the other NF-κB-inducing microbes, L. pneumophila activates NF-κB independently of IKKs and other cellular signaling components.…”

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

“…In contrast to the other NF-κB-inducing microbes, L. pneumophila activates NF-κB independently of IKKs and other cellular signaling components. Instead, it encodes a kinase, LegK1, which phosphorylates IκBα and p100, leading to the activation of canonical and non-canonical NF-κB pathways [106].…”

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

Non-canonical NF-κB signaling pathway

2010

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The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

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A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors

Abstract: NF-B is critical in innate immuneinnate immunity ͉ Legionella pneumophila ͉ p100 processing ͉ Type IV secretion ͉ bacterial pathogenesis

Cited by 149 publications

References 34 publications

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Non-canonical NF-κB signaling pathway

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