The tripartite motif (TRIM) protein family comprises more than 60 members that have diverse functions in various biological processes. Although a small number of TRIM proteins have been shown to regulate innate immunity, much remains to be learned about the functions of the majority of the TRIM proteins. Here we identify TRIM56 as a cellular protein associated with the N-terminal protease (N pro ) of bovine viral diarrhea virus (BVDV), a pestiviral interferon antagonist which degrades interferon regulatory factor 3 (IRF3) through the proteasome. We found that TRIM56 was constitutively expressed in most tissues, and its abundance was further upregulated moderately by interferon or virus. The manipulation of TRIM56 abundance did not affect the protein turnover of N pro and IRF3. Rather, ectopic expression of TRIM56 substantially impaired, while knockdown of TRIM56 expression greatly enhanced, BVDV replication in cell culture. The antiviral activity of TRIM56 depended on its E3 ubiquitin ligase activity as well as the integrity of its C-terminal region but was not attributed to a general augmentation of the interferon antiviral response. Overexpression of TRIM56 did not inhibit the replication of vesicular stomatitis virus or hepatitis C virus, a virus closely related to BVDV. Together, our data demonstrate that TRIM56 is a novel antiviral host factor that restricts pestivirus infection.The tripartite motif (TRIM) protein family consists of more than 60 members that have diverse functions in a broad range of biological processes, including, but not limited to, cell proliferation, differentiation, development, apoptosis, and immunity (19,21). Proteins of the TRIM family share the characteristic tripartite (also known as RBCC) motif that comprises a RING finger, one or two B boxes, and a coiled-coil domain at the N-terminal region. The C-terminal half, however, is variable among different TRIM proteins and can have or not have one or more specific domains that determine the function specificity of some TRIM members. Based on the C-terminal domain composition of the N-terminal RBCC motif, the human TRIMs are classified into 11 subfamilies, subfamilies C-I to C-XI, with the C-IV group having the largest number of members, all of which contain the SPRY/B30.2-like domain, a conserved region whose function remains unclear but is thought to be involved in protein-protein interactions or RNA binding (21,22,29).The functions of the majority of the TRIM proteins are poorly understood. Based on the presence of the RING domain, it was proposed that the TRIM proteins represent a novel class of single-RING-finger E3 ubiquitin (Ub) ligases that mediate the posttranslational modification of different substrates (18). By self-association via the coiled-coil domains, the TRIM proteins oligomerize and act as a scaffold for the assembly of multiprotein complexes that occupy specific cellular compartments (24). TRIM proteins have been shown to be involved in neurological diseases, genetic disorders, and carcinogenesis (18) and have rece...

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Background:The role of TRIM56 in innate antiviral immunity is unclear. Results: Knockdown of TRIM56 impairs TLR3-dependent IRF3 activation, interferon-stimulated gene expression and induction of antiviral responses, while overexpression of TRIM56 enhances TLR3-mediated innate immune responses. Conclusion: TRIM56 interacts with TRIF and promotes TLR3 signaling. Significance: This study identifies TRIM56 as an essential component of the TLR3 antiviral signaling pathway.

The tripartite motif-containing (TRIM) proteins have emerged as a new class of host antiviral restriction factors, with several demonstrating roles in regulating innate antiviral responses. Of >70 known TRIMs, TRIM56 inhibits replication of bovine viral diarrhea virus, a ruminant pestivirus of the family Flaviviridae, but has no appreciable effect on vesicular stomatitis virus (VSV), a rhabdovirus. Yet the antiviral spectrum of TRIM56 remains undefined. In particular, how TRIM56 impacts human-pathogenic viruses is unknown. Also unclear are the molecular determinants governing the antiviral activities of TRIM56. Herein, we show that TRIM56 poses a barrier to infections by yellow fever virus (YFV), dengue virus serotype 2 (DENV2), and human coronavirus virus (HCoV) OC43 but not encephalomyocarditis virus (EMCV). Moreover, by engineering cell lines conditionally expressing various TRIM56 mutants, we demonstrated that TRIM56's antiflavivirus effects required both the E3 ligase activity that lies in the N-terminal RING domain and the integrity of its C-terminal portion, while the restriction of HCoV-OC43 relied upon the TRIM56 E3 ligase activity alone. Furthermore, TRIM56 was revealed to impair YFV and DENV2 propagation by suppressing intracellular viral RNA accumulation but to compromise HCoV-OC43 infection at a later step in the viral life cycle, suggesting that distinct TRIM56 domains accommodate differing antiviral mechanisms. Altogether, TRIM56 is a versatile antiviral host factor that confers resistance to YFV, DENV2, and HCoV-OC43 through overlapping and distinct molecular determinants. IMPORTANCEWe previously reported tripartite motif protein 56 (TRIM56) as a host restriction factor of bovine viral diarrhea virus, a ruminant pathogen. However, the impact of TRIM56 on human-pathogenic RNA viruses is unknown. Herein, we demonstrate that TRIM56 restricts two medically important flaviviruses, yellow fever virus (YFV) and dengue virus serotype 2 (DENV2), and a human coronavirus, HCoV-OC43, but not encephalomyocarditis virus, a picornavirus. Further, we show that TRIM56-mediated inhibition of HCoV-OC43 multiplication depends solely on its E3 ligase activity, whereas its restriction of YFV and DENV2 requires both the E3 ligase activity and integrity of the C-terminal portion. The differing molecular determinants appear to accommodate distinct antiviral mechanisms TRIM56 adopts to target different families of viruses; while TRIM56 curbs intracellular YFV/DENV2 RNA replication, it acts at a later step in HCoV-OC43 life cycle. These novel findings illuminate the molecular basis of the versatility and specificity of TRIM56's antiviral activities against positive-strand RNA viruses.

Accumulating data suggest that tripartite-motif-containing (TRIM) proteins participate in host responses to viral infections, either by acting as direct antiviral restriction factors or through regulating innate immune signaling of the host. Of >70 TRIMs, TRIM56 is a restriction factor of several positive-strand RNA viruses, including three members of the family Flaviviridae (yellow fever virus, dengue virus, and bovine viral diarrhea virus) and a human coronavirus (OC43), and this ability invariably depends upon the E3 ligase activity of TRIM56. However, the impact of TRIM56 on negative-strand RNA viruses remains unclear. Here, we show that TRIM56 puts a check on replication of influenza A and B viruses in cell culture but does not inhibit Sendai virus or human metapneumovirus, two paramyxoviruses. Interestingly, the anti-influenza virus activity was independent of the E3 ligase activity, B-box, or coiled-coil domain. Rather, deletion of a 63-residue-long C-terminal-tail portion of TRIM56 abrogated the antiviral function. Moreover, expression of this short C-terminal segment curtailed the replication of influenza viruses as effectively as that of full-length TRIM56. Mechanistically, TRIM56 was found to specifically impede intracellular influenza virus RNA synthesis. Together, these data reveal a novel antiviral activity of TRIM56 against influenza A and B viruses and provide insights into the mechanism by which TRIM56 restricts these medically important orthomyxoviruses. IMPORTANCE Options to treat influenza are limited, and drug-resistant influenza virus strains can emerge through minor genetic changes. Understanding novel virus-host interactions that alter influenza virus fitness may reveal new targets/approaches for therapeutic interventions.We show here that TRIM56, a tripartite-motif protein, is an intrinsic host restriction factor of influenza A and B viruses. Unlike its antiviral actions against positive-strand RNA viruses, the anti-influenza virus activity of TRIM56 was independent of the E3 ligase activity. Rather, expression of a short segment within the very C-terminal tail of TRIM56 inhibited the replication of influenza viruses as effectively as that of full-length TRIM56 by specifically targeting viral RNA synthesis. These data reveal the remarkable multifaceted activity of TRIM56, which has developed multiple domains to inhibit multiple viral families. They also raise the possibility of developing a broad-spectrum, TRIM56-based antiviral approach for addition to influenza prophylaxis and/or control strategies.

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Significance Here, we present data showing that monocyte chemotactic protein-induced protein 1 (MCPIP1) acts as an RNase to limit HIV-1 production in resting CD4+ T cells. Unlike those previously identified factors with restrictions that tend to be overcome by virally encoded proteins, MCPIP1 becomes rapidly degraded on activation of human CD4+ T cells. These findings provide insights into the mechanisms of cellular activation-mediated HIV-1 production in CD4+ T cells and represent a breakthrough in the relevant field.

Metal–organic frameworks (MOFs) have been attracting a great deal of attention as potential solid electrolytes (SEs). However, the interfacial compatibility of MOF-based SEs caused by the physical contact among MOF particles, the polymer binder, and electrodes is not yet fully determined. Herein, a bioinspired design strategy aiming to build ion transport pathways at interfaces was introduced. The MOF-to-MOF transport paths were built via in situ ring opening of epoxide, akin to the protein molecules that transport the ion across the cell walls. After optimization, the obtained SE is endowed with a high ion conductivity of 1.70 × 10–3 S cm–1 at 30 °C, a wide electrochemical window of 4.6 V, a high Li+ transference number of 0.8, and a decreased interface resistance. Consequently, the fabricated quasi-solid metal batteries exhibit higher and more stable cycling performance compared to the performance of those without interface optimization. This strategy for optimizing the interfacial compatibility of MOFs thus exploits a new avenue for developing high-performance SEs for various metal batteries.