HyperService: Interoperability and Programmability Across Heterogeneous Blockchains

Blockchain interoperability, which allows state transitions across different blockchain networks, is critical functionality to facilitate major blockchain adoption. Existing interoperability protocols mostly focus on atomic token exchange between blockchains. However, as blockchains have been upgraded from passive distributed ledgers into programmable state machines (thanks to smart contracts), the scope of blockchain interoperability goes beyond just token exchange. In this paper, we present HyperService, the first platform that delivers interoperability and programmability across heterogeneous blockchains. HyperService is powered by two innovative designs: (i) a developer-facing programming framework that allows developers to build cross-chain applications in a unified programming model; and (ii) a secure blockchain-facing cryptography protocol that provably realizes those applications on blockchains. We implement a prototype of HyperService in about 35,000 lines of code to demonstrate its practicality. Our experiment results show that HyperService imposes reasonable latency, in order of seconds, on the end-to-end execution of cross-chain applicationsComment: An extended version of the material published in ACM CCS 201

MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

The RIG-I-like receptors (RLRs) signaling pathway is essential for inducing type I interferon (IFN) responses to viral infections. Meanwhile, it is also tightly regulated to prevent uncontrolled immune responses. Numerous studies have shown that microRNAs (miRNAs) are essential for the regulation of immune processes, however, the detailed molecular mechanism of miRNA regulating the RLRs signaling pathway remains to be elucidated. Here, our results showed that miR-202-5p was induced by red spotted grouper nervous necrosis virus (RGNNV) infection in zebrafish. Overexpression of miR-202-5p led to reduced expression of IFN 1 and its downstream antiviral genes, thus facilitating viral replication in vitro. In comparison, significantly enhanced levels of IFN 1 and antiviral genes and significantly low viral burden were observed in the miR-202-5p-/- zebrafish compared to wild type zebrafish. Subsequently, zebrafish tripartite motif-containing protein 25 (zbTRIM25) was identified as a target of miR-202-5p in both zebrafish and humans. Ectopic expression of miR-202-5p suppressed zbTRIM25-mediated RLRs signaling pathway. Furthermore, we showed that miR-202-5p inhibited zbTRIM25-mediated zbRIG-I ubiquitination and activation of IFN production. In conclusion, we demonstrate that RGNNV-inducible miR-202-5p acts as a negative regulator of zbRIG-I-triggered antiviral innate response by targeting zbTRIM25. Our study reveals a novel mechanism for the evasion of the innate immune response controlled by RGNNV

Marine medaka heat shock protein 90ab1 is a receptor for red-spotted grouper nervous necrosis virus and promotes virus internalization through clathrin-mediated endocytosis.

Nervous necrosis virus (NNV) can infect many species of fish and causes serious acute or persistent infection. However, its pathogenic mechanism is still far from clear. Specific cellular surface receptors are crucial determinants of the species tropism of a virus and its pathogenesis. Here, the heat shock protein 90ab1 of marine model fish species marine medaka (MmHSP90ab1) was identified as a novel receptor of red-spotted grouper NNV (RGNNV). MmHSP90ab1 interacted directly with RGNNV capsid protein (CP). Specifically, MmHSP90ab1 bound to the linker region (LR) of CP through its NM domain. Inhibition of MmHSP90ab1 by HSP90-specific inhibitors or MmHSP90ab1 siRNA caused significant inhibition of viral binding and entry, whereas its overexpression led to the opposite effect. The binding of RGNNV to cultured marine medaka hMMES1 cells was inhibited by blocking cell surface-localized MmHSP90ab1 with anti-HSP90β antibodies or pretreating virus with recombinant MmHSP90ab1 or MmHSP90ab1-NM protein, indicating MmHSP90ab1 was an attachment receptor for RGNNV. Furthermore, we found that MmHSP90ab1 formed a complex with CP and marine medaka heat shock cognate 70, a known NNV receptor. Exogenous expression of MmHSP90ab1 independently facilitated the internalization of RGNNV into RGNNV impenetrable cells (HEK293T), which was blocked by chlorpromazine, an inhibitor of clathrin-dependent endocytosis. Further study revealed that MmHSP90ab1 interacted with the marine medaka clathrin heavy chain. Collectively, these data suggest that MmHSP90ab1 is a functional part of the RGNNV receptor complex and involved in the internalization of RGNNV via the clathrin endocytosis pathway