GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses

Kashyap, Abhishek S.; Fernandez-Rodriguez, Laura; Zhao, Yun; Monaco, Gianni; Trefny, Marcel P.; Yoshida, Naohiro; Martin, Kea; Sharma, Ashwani; Olieric, Natacha; Shah, Pankaj; Stanczak, Michal A.; Kirchhammer, Nicole; Park, Sung-Moo; Wieckowski, Sébastien; Läubli, Heinz; Zagani, Rachid; Kasenda, Benjamin; Steinmetz, Michel O.; Reinecker, Hans Christian; Zippelius, Alfred

doi:10.1016/j.celrep.2019.08.057

Cited by 41 publications

(49 citation statements)

References 69 publications

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“…For instance, GEF-H1-driven activation of RhoA promotes actin polymerization, modulating cell contractility or endothelial barrier permeability [34][35][36]. Notably, GEF-H1 participates in the activation of NF-κB during intracellular pathogen recognition [37,38] or in response to microtubule destabilization [39]. Supporting previous works [37,38], we observed that the overexpression of GEF-H1 in HEK293T was sufficient to promote the transcriptional activity of NF-κB ( Fig.…”

Section: Resultssupporting

confidence: 84%

The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

Douanne

Chapelier

Rottapel

et al. 2020

Preprint

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The natural bioactive glycerophospholipid lysophosphatidic acid (LPA) binds to its cognate G protein-coupled receptors (GPCRs) on the cell surface to promote the activation of several transcription factors, including NF-κB. LPA-mediated activation of NF-κB relies on the formation of a signalosome that contains the scaffold CARMA3, the adaptor BCL10 and the paracaspase MALT1 (CBM complex). The CBM has been extensively studied in lymphocytes, where it links antigen receptors to NF-κB activation via the recruitment of the linear ubiquitin assembly complex (LUBAC), a tripartite complex of HOIP, HOIL1 and SHARPIN. Moreover, MALT1 cleaves the LUBAC subunit HOIL1 to further enhance NF-κB activation. However, the contribution of the LUBAC downstream of GPCRs has not been investigated. By using murine embryonic fibroblasts from mice deficient for HOIP, HOIL1 and SHARPIN, we report that the LUBAC is crucial for the activation of NF-κB in response to LPA. Further echoing the situation in lymphocytes, LPA unbridles the protease activity of MALT1, which cleaves HOIL1 at the Arginine 165. The expression of a MALT1-insensitive version of HOIL1 reveals that this processing is required for the optimal production of the NF-κB target cytokine interleukin-6. Lastly, we provide evidence that the guanine exchange factor GEF-H1 activated by LPA favors MALT1-mediated cleavage of HOIL1 and NF-κB signaling. Together, our results unveil a critical role for the LUBAC as a positive regulator of NF-κB signaling downstream of GPCRs.

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Section: Resultssupporting

confidence: 84%

The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

Douanne

Chapelier

Rottapel

et al. 2020

Preprint

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“…Here we have shown that while the presence of tumors or treatment with docetaxel did not significantly affect LSK number in the bone marrow of mice, adding plinabulin to docetaxel in tumor-bearing mice resulted in a significant increase in LSK cell number within 2 days. Interestingly, the finding that both plinabulin and LPS [20,22] increased bone marrow LSK number in Balb/c mice is reminiscent of their common ability to mature dendritic cells, possibly indicating overlapping molecular signaling pathways [13].…”

Section: Discussionmentioning

confidence: 99%

“…Plinabulin reversibly binds to β-tubulin within the colchicine pocket [10], preventing polymerization into microtubules [11]. Following microtubule disruption, plinabulin exerts diverse cellular effects ranging from direct killing of cancer cells and proliferating endothelial cells [11,12], to increasing dendritic cell maturation [13]. Importantly, plinabulin significantly reduced CIN in cancer patients when administered within 1 h following treatment with another tubulintargeted therapy, docetaxel (Taxotere ® ) [9] [Mohanlal et al, ASCO-SITC 2018, Abstract 126].…”

Section: Introductionmentioning

confidence: 99%

Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies

Tonra¹,

Lloyd²,

Mohanlal³

et al. 2019

Cancer Chemother Pharmacol

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Purpose Chemotherapy-induced neutropenia (CIN) increases the risk of infections and mortality in cancer patients. G-CSF therapies are approved for the treatment of CIN, but non-G-CSF therapies are needed to increase efficacy and minimize side effects. Plinabulin is an inhibitor of tubulin polymerization that ameliorates CIN caused in patients by the microtubule stabilizer docetaxel. The present study evaluates the potential of plinabulin to reduce neutropenia induced by chemotherapies of different classes in a manner not dependent on increasing G-CSF. Methods The anti-CIN benefits of plinabulin were tested in rodents co-treated with docetaxel, cyclophosphamide or doxorubicin. Effects on G-CSF levels were evaluated in tissues by immunoassay. Flow cytometry was utilized to test treatment effects on femur bone marrow cell counts from immunocompetent mice-bearing orthotopic 4T1 breast cancer tumors. Results Plinabulin alleviated neutropenia induced by microtubule stabilizing, DNA cross-linking and DNA intercalating chemotherapies, yet did not affect bone marrow or blood G-CSF levels. The number of lineage − /Sca1 + /c-Kit + (LSK) hematopoietic stem/progenitor cells (HSPC) in murine bone marrow collected 2 days after treatment was not affected by docetaxel monotherapy despite increased plasma G-CSF in this group. LSK cell number was, however, increased when plinabulin was combined with docetaxel, without affecting G-CSF. Conclusions Results support the clinical testing of plinabulin as a non-G-CSF-based treatment for CIN associated with chemotherapies of different mechanisms. Results also support HSPC as a focal point for future mechanism-of-action work aimed at understanding the ability of plinabulin to reduce this serious side effect of cytotoxic therapy in cancer patients.

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“…Notably, colchicine has been shown to attenuate the production of IL-1β in response to MSU-induced NLRP3 activation [10]. Given microtubule-associated immune molecule GEF-H1 is released upon the treatment of microtubule destabilization agent colchicine [17,19], this prompted us to perform a detailed investigation of NLRP3 inflammasome activation in WT and GEF-H1-deficient macrophages. We first examined the expression of core NLRP3 inflammasome components in both WT and GEF-H1-deficient BMDMs.…”

Section: Deficiency Of Gef-h1 Does Not Affect the Secretion Of Il-1β mentioning

confidence: 99%

“…The activation of GEF-H1 has been linked to several cellular processes, such as cell shape, polarization, differentiation, movement, cell cycle regulation, and epithelial barrier permeability by coupling microtubule dynamics to RhoA GTPase activation [17]. Moreover, alteration of GEF-H1 activity is implicated in the pathogenesis of cancer [18,19]. In addition, GEF-H1 is activated and released from microtubules upon the intracellular binding of bacterial effectors [20,21] and subsequently contributes to the recognition of intracellular bacteria through cytosolic pattern recognition receptors NOD1 and NOD2 [20,22,23].…”

Section: Introductionmentioning

confidence: 99%

Microtubule-Mediated NLRP3 Inflammasome Activation Is Independent of Microtubule-Associated Innate Immune Factor GEF-H1 in Murine Macrophages

Lai

Hsu

Lee

et al. 2020

IJMS

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Inflammasomes are intracellular multiple protein complexes that mount innate immune responses to tissue damage and invading pathogens. Their excessive activation is crucial in the development and pathogenesis of inflammatory disorders. Microtubules have been reported to provide the platform for mediating the assembly and activation of NLRP3 inflammasome. Recently, we have identified the microtubule-associated immune molecule guanine nucleotide exchange factor-H1 (GEF-H1) that is crucial in coupling microtubule dynamics to the initiation of microtubule-mediated immune responses. However, whether GEF-H1 also controls the activation of other immune receptors that require microtubules is still undefined. Here we employed GEF-H1-deficient mouse bone marrow-derived macrophages (BMDMs) to interrogate the impact of GEF-H1 on the activation of NLRP3 inflammasome. NLRP3 but not NLRC4 or AIM2 inflammasome-mediated IL-1β production was dependent on dynamic microtubule network in wild-type (WT) BMDMs. However, GEF-H1 deficiency did not affect NLRP3-driven IL-1β maturation and secretion in macrophages. Moreover, α-tubulin acetylation and mitochondria aggregations were comparable between WT and GEF-H1-deficient BMDMs in response to NLRP3 inducers. Further, GEF-H1 was not required for NLRP3-mediated immune defense against Salmonella typhimurium infection. Collectively, these findings suggest that the microtubule-associated immune modulator GEF-H1 is dispensable for microtubule-mediated NLRP3 activation and host defense in mouse macrophages.

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GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses

Cited by 41 publications

References 69 publications

The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies

Microtubule-Mediated NLRP3 Inflammasome Activation Is Independent of Microtubule-Associated Innate Immune Factor GEF-H1 in Murine Macrophages

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