RIG-I is a critical RNA virus sensor that serves to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling remains to be fully understood. We report here that RNA viruses, but not DNA viruses or bacteria, specifically upregulate lectin family member Siglecg expression in macrophages by RIG-I- or NF-κB-dependent mechanisms. Siglec-G-induced recruitment of SHP2 and the E3 ubiquitin ligase c-Cbl to RIG-I leads to RIG-I degradation via K48-linked ubiquitination at Lys813 by c-Cbl. By increasing type I interferon production, targeted inactivation of Siglecg protects mice against lethal RNA virus infection. Taken together, our data reveal a negative feedback loop of RIG-I signaling and identify a Siglec-G-mediated immune evasion pathway exploited by RNA viruses with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of Siglec-G, a known adaptive response regulator, in innate immunity.
Samarium supersensors
Piezoelectric materials produce electric charge in response to changes in stress and are thus good sensor materials. One challenge has been growing single-crystal piezoelectrics with uniform properties. As of now, much of the crystal is discarded because of compositional variations. Li
et al.
synthesized single crystals of samarium-doped Pb(Mg
1/3
Nb
2/3
)O
3
-PbTiO
3
that have uniform and extremely high piezoelectric properties (see the Perspective by Hlinka). These crystals are ideal for a variety of sensing applications and could reduce cost by eliminating waste.
Science
, this issue p.
264
; see also p.
228
How the intestinal tract develops a tolerance to foreign antigens is still largely unknown. Here we report that extracellular vesicles (EVs) with TGF-β1-dependent immunosuppressive activity are produced by intestinal epithelial cells (IECs) under physiological conditions. Transfer of these EVs into inflammatory bowel disease (IBD) mice induced by dextran sulfate sodium salt decreases IBD severity by inducing regulatory T cells and immunosuppressive dendritic cells. In contrast, decreased endogenous EV production promotes IBD development. IECs produce EVs with increased levels of TGF-β1 upon IBD development in an ERK-dependent manner. Furthermore, these EVs tend to localize in the intestinal tract associated with epithelial cell adhesion molecule (EpCAM). Knockdown of EpCAM in vivo increases the severity of murine IBD, and the protective effect of EVs from IECs with decreased EpCAM on murine IBD is blunted. Therefore, our study indicates that EVs from IECs participate in maintaining the intestinal tract immune balance.
Graphical Abstract Highlights d CD19 + EVs through CD39 and CD73 hydrolyze ATP from tumor cells into adenosine d CD19 + EVs blunt post-chemotherapeutic CD8 T cell responses via adenosine d Tumor B cells produce more EVs by enhancing HIF-1a-mediated Rab27a transcription d IEBVs-Rab27a siRNA is a potential tool for improving chemotherapeutic effect SUMMARY Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19 + extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8 + T cell responses. Serum CD19 + EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19 + EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1a (HIF-1a) promoted B cells to release CD19 + EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1a deficiency in B cells inhibited CD19 + EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD Prkdc scid Il2rg À/À mice. Thus, decreasing CD19 + EVs holds high potential to improve the chemotherapeutic antitumor effect.
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