TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

AbstractSpleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

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Role of FGFR2b in the crosstalk between autophagy and differentiation: involvement of JNK signaling.

Molecular and Cellular Biology ◽

10.1128/mcb.00119-18 ◽

2018 ◽

pp. MCB.00119-18 ◽

Cited By ~ 2

Author(s):

Monica Nanni ◽

Danilo Ranieri ◽

Benedetta Rosato ◽

Maria Rosaria Torrisi ◽

Francesca Belleudi

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Molecular Mechanisms ◽

Akt Signaling ◽

Epidermal Differentiation ◽

Keratinocyte Differentiation ◽

Jnk Pathway ◽

Jnk Signaling ◽

Early Differentiation

The FGFR2b is a receptor tyrosine kinase expressed exclusively in epithelial cells. We previously demonstrated that FGFR2b induces autophagy and that this process is required for the triggering of FGFR2b-mediated keratinocytes early differentiation. However, the molecular mechanisms regulating this interplay remain to be elucidated. Since we have also recently shown that JNK1 signaling is involved in FGFR2b-induced autophagy and a possible role of JNK pathway in epidermal differentiation has been suggested but it is still debated, here we investigated the crosstalk between FGFR2b-mediated autophagy and differentiation focusing on the downstream JNK signaling. Biochemical, molecular and immunofluorescence approaches in 2D keratinocyte cultures and 3D organotypic skin equivalents confirmed that FGFR2b overexpression increased both autophagy and early differentiation. The use of FGFR2b substrate inhibitors and the silencing of JNK1 highlighted that this signaling is required not only for autophagy but also for the triggering of early differentiation. In contrast, ERK1/2 pathway did not appear to be involved in the two processes and AKT signaling, whose activation contributes to the FGFR2b-mediated onset of keratinocyte differentiation, was not required for the triggering of autophagy. Overall, our results point to JNK1 as a signaling hub that regulates the interplay between FGFR2b-induced autophagy and differentiation.

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Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180723104340 ◽

2019 ◽

Vol 14 (3) ◽

pp. 219-225 ◽

Cited By ~ 6

Author(s):

Cong Tang ◽

Guodong Zhu

Keyword(s):

Cancer Therapy ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Cell Receptor ◽

Transmembrane Receptors ◽

Biological Responses ◽

Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

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