Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

Zheng, Qi-Teng; Hou, Jin; Zhou, Ye; Yang, Yingyun; Xie, Bing; Cao, Xuetao

doi:10.1038/cr.2015.108

Cited by 151 publications

(129 citation statements)

References 41 publications

(51 reference statements)

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“…Siglecs which lack an ITIM domain (such as Siglec-14, 15, and 16) associate with DAP12 via a positively charged amino acid in their transmembrane region to activate receptors through the recruitment of Syk (15,40). Siglec-1, the first discovered member of Siglecs, has been shown to play an important role in sialylated pathogen uptake (17,19,(53)(54)(55), antigen presentation (56,57), lymphocyte proliferation (58), self-tolerance (59,60) and antiviral immune response (47). However, the biological function of Siglec-1 in endotoxin tolerance is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was reported that Siglec-1 is associated with DAP12 in VSV-infected macrophages to control the antiviral innate immune response (47). We next examined whether Siglec-1, DAP12, and Syk form a complex to regulate the production of TGF-␤1 in RAW 264.7 cells after induction of endotoxin tolerance.…”

Section: Down-regulation Of Siglec-1 Promotes Degradation Of Syk By Imentioning

confidence: 99%

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Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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Section: Discussionmentioning

confidence: 99%

Section: Down-regulation Of Siglec-1 Promotes Degradation Of Syk By Imentioning

confidence: 99%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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“…Interestingly, we previously found that Siglec1 and TRIM27 are negative regulators of VSV-triggered type I IFN production (11). Phenocopying the effect of miR-27a overexpression, both Siglec1 and TRIM27 knockdown significantly increased VSV-triggered type I IFN production and accordingly inhibited VSV replication (11).…”

Section: Antiviral Function Of Mir-27a Is Mainly Through Targeting Simentioning

confidence: 99%

“…For example, sialic acid-binding Ig-like lectin (Siglec)-G negatively regulates type I IFN production in the innate response against RNA virus infection by promoting retinoic acid-inducible gene I (RIG-I) proteasomal degradation (10). We previously found that Siglec1 associated with DNAX activation protein-12 to activate the scaffolding function of Src homology 2 domain-containing protein tyrosine phosphatase 2, and then recruited E3 ligase tripartite motif-containing protein 27 (TRIM27) to degrade TBK1, thus negatively regulating type I IFN production (11). Hence, type I IFN production during viral infection should be tightly controlled to initiate an appropriate immune response that eliminates invading pathogens but to avoid excessive production of type I IFN-mediated immunopathological conditions or immune disorders (12,13).…”

mentioning

confidence: 99%

Type I IFN–Inducible Downregulation of MicroRNA-27a Feedback Inhibits Antiviral Innate Response by Upregulating Siglec1/TRIM27

Zheng

Hou

Zhou

et al. 2016

The Journal of Immunology

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Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid–inducible gene I–like helicases, cells are activated to produce type I IFN, which plays key roles in host antiviral innate immune response. However, excessive IFN production may induce immune disorders, and the mechanisms responsible for the regulation of type I IFN production have attracted much attention. Furthermore, type I IFN activates the downstream IFN/JAK/STAT pathway to modulate expression of a set of genes against viral infection, but whether these genes can feedback regulate type I IFN production is poorly understood. In this study, by screening the microRNAs modulated by viral infection in macrophages, we identified that microRNA (miR)-27a was significantly downregulated via the IFN/JAK/STAT1/runt-related transcription factor 1 pathway. Inducible downregulation of miR-27a, in turn, negatively regulated vesicular stomatitis virus–triggered type I IFN production, thus promoting vesicular stomatitis virus replication in macrophages. Mechanistically, we found that miR-27a directly targeted sialic acid–binding Ig-like lectin (Siglec)1 and E3 ubiquitin ligase tripartite motif–containing protein 27 (TRIM27), both of which were previously verified as negative regulators of type I IFN production. Furthermore, we constructed “Sponge” transgenic mice against miR-27a expression and found that Siglec1 and TRIM27 expression were elevated whereas type I IFN production was inhibited and viral replication was aggregated in vivo. Therefore, type I IFN–induced downregulation of miR-27a can upregulate Siglec1 and TRIM27 expression, feedback inhibiting type I IFN production in antiviral innate response. Our study outlines a new negative way to feedback regulate type I IFN production.

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“…For example, DNA methyltransferase Dnmt3a selectively upregulates the production of type I interferons by maintaining high expression of HDAC9 to deacetylate TBK1 for activation of antiviral innate immunity . RNA viruses can specifically upregulate the expression of Siglec-G (Chen et al, 2013b), Siglec1 (Zheng et al, 2015) and DAPK1 (Zhang et al, 2014a) which regulate antiviral innate immune response. Cytoplasmic STAT4 has been described to interact with E3 ligase CHIP and block RIG-I and CHIP association, resulting in preventing CHIP-mediated proteasomal degradation of RIG-I .…”

Section: Regulation Of Rlr Signaling Pathwaysmentioning

confidence: 99%

Innate recognition of microbial-derived signals in immunity and inflammation

Zhang

Liang

2016

Sci. China Life Sci.

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Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

Cited by 151 publications

References 41 publications

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Type I IFN–Inducible Downregulation of MicroRNA-27a Feedback Inhibits Antiviral Innate Response by Upregulating Siglec1/TRIM27

Innate recognition of microbial-derived signals in immunity and inflammation

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