E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor–mediated antifungal innate immunity

Zhu, Lele; Luo, Tian Ming; Xu, Xiaolong; Guo, Yin; Zhao, Xue Qiang; Wang, Ting Ting; Tang, Bin; Jiang, Yuan; Xu, Jin; Lin, Xin; Jia, Xiaomin

doi:10.1084/jem.20151932

Cited by 48 publications

(63 citation statements)

References 53 publications

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“…As these CLRs lack a signaling domain, heterodimeric complexes signal via the ITAM-coupled adaptor FcRγ (9). Following fungal recognition, the E3 ubiquitin ligase CBLB ubiquitinates dectin-1, dectin-2, and SYK, targeting them for degradation (50)(51)(52). In systemic candidiasis, Cblb -/-mice exhibit reduced renal fungal burden and improved survival due to decreased inflammation-driven tissue damage (50)(51)(52).…”

Section: Introductionmentioning

confidence: 99%

“…Following fungal recognition, the E3 ubiquitin ligase CBLB ubiquitinates dectin-1, dectin-2, and SYK, targeting them for degradation (50)(51)(52). In systemic candidiasis, Cblb -/-mice exhibit reduced renal fungal burden and improved survival due to decreased inflammation-driven tissue damage (50)(51)(52). In contrast, TRIM62-mediated CARD9 ubiquitination is essential for BCL10 interactions, NF-κB activation, and defense against candidiasis (53).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

109

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

109

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“…Cbl-mediated polyubiquitination leads to protein degradation via the lysosome and proteasome (56). Cbl-family ligases must in turn be tightly regulated to prevent hyperresponsive or aberrant signaling while maintaining proper pathogen clearance (57). Although highly homologous, c-Cbl and Cbl-b target different subsets of signaling proteins for degradation (58, 59), with c-Cbl targeting the SFKs, including Lyn (60, 61), and Cbl-b interacting with ITAM-coupled receptors and other kinases (31, 53, 57).…”

Section: Discussionmentioning

confidence: 99%

“…Cbl-family ligases must in turn be tightly regulated to prevent hyperresponsive or aberrant signaling while maintaining proper pathogen clearance (57). Although highly homologous, c-Cbl and Cbl-b target different subsets of signaling proteins for degradation (58, 59), with c-Cbl targeting the SFKs, including Lyn (60, 61), and Cbl-b interacting with ITAM-coupled receptors and other kinases (31, 53, 57). c-Cbl is thought to interact with active SFKs through the SFK activation-loop phosphotyrosine residue, which binds the c-Cbl PTB domain (62), and through the SFK SH3 domain, which binds the c-Cbl PXXP motifs (63).…”

Section: Discussionmentioning

confidence: 99%

An orthogonal c-Cbl recognition mode targets LynA for rapid degradation and builds specificity into the LynA checkpoint

Brian

Nunez

Schwertfeger

et al. 2019

Preprint

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11The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based 12 activation motifs (ITAMs), is critical factor regulating myeloid-cell activation. In a previous paper 13 (Freedman et al., 2015) we showed in macrophages that the SFK LynA is uniquely susceptible to rapid 14 ubiquitin-mediated degradation, functioning as a rheostat regulating ITAM signaling. We now report the 15 mechanism by which LynA is preferentially targeted for degradation and how cell specificity is built into 16 the LynA rheostat. Using genetic and biochemical analysis, we found that the E3 ubiquitin ligase c-Cbl 17 preferentially targets LynA via tyrosine 32 in its unique insert region. This orthogonal mode of c-Cbl 18 recognition depresses the steady-state level of macrophage LynA. Mast cells, however, express little c- 19Cbl and have correspondingly high steady-state levels of LynA. Upon activation, mast-cell LynA is not 20 rapidly degraded, and SFK-mediated signaling is amplified relative to macrophages. Cell-specific c-Cbl 21 expression therefore builds cell specificity into the LynA checkpoint. 2245 macrophage activation (20). The mechanism preferentially targeting LynA for polyubiquitination and the 46 molecular basis of this selectivity have not been elucidated previously. 47Unlike Dectin-1 and FcγR signaling in macrophages, which is typically triggered in the context of 48 pathogen-induced µm-scale clusters of receptors (5, 9, 20), mast-cell FcεR signaling has a low 49 threshold for activation--small or even monovalent antigen-IgE complexes are sufficient to induce a 50 signaling response (21, 22). Like macrophages, mast cells express LynA, and this disparity in receptor 51 sensitivity has not previously been explained. This paper describes the mechanism by which active LynA is selectively recognized and rapidly 53 degraded, tuning its activation kinetics and its steady-state protein levels in a cell-specific manner. To 54 reveal the requirements for LynA degradation, we synchronized receptor-independent SFK activation 55 using the designer inhibitor 3-IB-PP1 (23-25), which specifically inhibits a variant of the SFK-inhibitory 56 kinase Csk (Csk AS ) (20, 25, 26). Csk is responsible for phosphorylating a key inhibitory tyrosine in the 57 C-terminus of all the SFKs. Inhibiting Csk AS leads to rapid and robust SFK activation due to the loss of 58 the dynamic equilibrium between Csk and the phosphatases CD45 and CD148 (27, 28). We showed 59 previously that SFK activation induced via 3-IB-PP1 treatment leads to the phosphorylation of the E3 60 ubiquitin ligase c-Cbl and the preferential polyubiquitination and degradation of the SFK LynA, but it 61 was not clear whether these two events were linked. Using knockdown, overexpression, and genetic 62 models, we now demonstrate that c-Cbl, but not its homolog Cbl-b, controls the steady-state expression 63 of LynA and mediates its rapid degradation upon activation in macrophages. LynA is targeted by c-Cbl 64 via a phosphorylation site, Tyr32 within its unique r...

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“…1). Recently, 3 complementary studies showed that the E3 ubiquitin ligase CBLB targets dectin-1, dectin-2, macrophage C-type lectin (MCL) (described in more detail below), and their adaptor molecule Syk for degradation, and thus exerts a strong anti-inflammatory effect [7-9]. The authors showed that treatment strategies involving the inhibition of CBLB led to increased inflammatory responses and improved the outcome of experimental candidiasis, which provides evidence that CBLB might represent a therapeutic target in fungal disease.…”

Section: Dectin-1mentioning

confidence: 99%

Antifungal Innate Immunity: A Perspective from the Last 10 Years

Salazar¹,

Brown²

2018

J Innate Immun

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Fungal pathogens can rarely cause diseases in immunocompetent individuals. However, commensal and normally nonpathogenic environmental fungi can cause life-threatening infections in immunocompromised individuals. Over the last few decades, there has been a huge increase in the incidence of invasive opportunistic fungal infections along with a worrying increase in antifungal drug resistance. As a consequence, research focused on understanding the molecular and cellular basis of antifungal immunity has expanded tremendously in the last few years. This review will provide an overview of the most exciting recent advances in innate antifungal immunity, discoveries that are helping to pave the way for the development of new strategies that are desperately needed to combat these devastating diseases.

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E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor–mediated antifungal innate immunity

Abstract: Innate immune responses mediated by C-type lectin receptors Dectin-2 and Dectin-3 against fungal infections are negatively regulated by Cbl-b ubiquitination.

Cited by 48 publications

References 53 publications

Immunity against fungi

Immunity against fungi

An orthogonal c-Cbl recognition mode targets LynA for rapid degradation and builds specificity into the LynA checkpoint

Antifungal Innate Immunity: A Perspective from the Last 10 Years

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