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In vitro ubiquitination by E3 ligase Cbl-b

ABSTRACT: Fungal infections claim an estimated 1.5 million lives every year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLR) and their downstream signaling kinase SYK. Here we report that the E3-ubiquitin-ligase CBL-B controls proximal C-type lectin receptor signaling in macrophages and dendritic cells. We show that CBL-B associates with SYK and ubiquitinates SYK, Dectin-1, and Dectin-2 upon fungal recognition. Functionally, CBL-B deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival upon a lethal systemic infection with Candida albicans. Based on these findings, we engineered a cell-permeable CBL-B inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate anti-fungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Richard Imre

LAB HEAD: Josef Penninger

PROVIDER: PXD004256 | Pride | 2016-06-17

REPOSITORIES: Pride

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			Action	DRS
	20150807_QEx5_RSLC8_Asaoko_Ikeda_IMBA_coom_try_dig_50per_control_band_A1.raw	Raw
	20150807_QEx5_RSLC8_Asaoko_Ikeda_IMBA_coom_try_dig_50per_control_band_A1_MSAmanda_ident-human_ubi.msf	Msf
	20150807_QEx5_RSLC8_Asaoko_Ikeda_IMBA_coom_try_dig_50per_control_band_A2.raw	Raw
	20150807_QEx5_RSLC8_Asaoko_Ikeda_IMBA_coom_try_dig_50per_control_band_A2_MSAmanda_ident-human_ubi.msf	Msf
	20150807_QEx5_RSLC8_Asaoko_Ikeda_IMBA_coom_try_dig_50per_control_band_A3.raw	Raw

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in vitro ubiquitination by E3 ligase Cbl-b

Project description:Fungal infections claim an estimated 1.5 million lives every year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLR) and their downstream signaling kinase SYK. Here we report that the E3-ubiquitin-ligase CBL-B controls proximal C-type lectin receptor signaling in macrophages and dendritic cells. We show that CBL-B associates with SYK and ubiquitinates SYK, Dectin-1, and Dectin-2 upon fungal recognition. Functionally, CBL-B deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival upon a lethal systemic infection with Candida albicans. Based on these findings, we engineered a cell-permeable CBL-B inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate anti-fungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

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BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

Project description:B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.

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F1Fo-ATP synthase subunit determines lethal infection in pathogenic fungi

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Project description:Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections, but human anti-fungal immunity remains poorly defined. Expression profiling of Candida-stimulated human peripheral blood mononuclear cells (PBMCs) provides new insights into Candida-specific host defense mechanisms in humans. Total RNA was extracted from PBMCs from healthy human volunteers. PBMCs were stimulated with heat-killed Candida albicans (10^6/ml), non-fungal inflammatory stimuli or RPMI control for 4 or 24 hours. A large number of biological replicates (>20) were included per stimulation condition and duration.

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F1Fo-ATP synthase subunit determines lethal pathogenic fungi infection

Project description:Fungal infections, especially candidiasis and aspergillosis, claim an unacceptably high fatality rate. The energy ATP that is necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation, with the key enzyme being F1Fo-ATP synthase. But it remains unknown how this enzyme affects fungal pathogenicity. Here, we show that F1Fo-ATP synthase δ subunit deletion abrogates lethal Candida albicans infection without affecting intracellular ATP concentrations or growth. Mechanistically, δ subunit deletion reduces Pfk1 activity by interrupting Pfk1 phosphorylation to trigger its conformation shifts, decreases downstream FBP level, blocks Ras1-dependent and -independent cAMP-PKA pathways, and curtails virulence factors. Based on these findings, we engineer a small molecule compound targeting δ subunit that effectively protects mice from succumbing to invasive candidiasis. In summary, our findings reveal that F1Fo-ATP synthase δ subunit determines lethal infection from pathogenic fungi and represents a potential therapeutic target.

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