Ring Finger Protein 215 Negatively Regulates Type I IFN Production via Blocking NF-κB p65 Activation.

Germline-encoded pattern recognition receptors (PRRs) recognize molecules frequently found in pathogens (pathogen-associated molecular patterns [PAMPs]) during viral infection. This process induces production of IFNs, leading to expression of IFN-stimulated genes to establish a cellular antiviral state against viral infection. However, aberrant activation of the IFN system may cause immunopathological damage and systemic autoimmune diseases such as systemic lupus erythematosus. Stringent control of IFN signaling activation is critical for maintaining homoeostasis of the immune system; yet, the mechanisms responsible for its precise regulation remain to be elucidated. In this study, we identified that ring finger protein 215 (RNF215), a zinc finger protein, was upregulated by viral infection in human macrophages. In addition, we demonstrated that RNF215 inhibited the production of type I IFNs at least in part via interacting with p65, a subunit of NF-κB, and repressed the accumulation of NF-κB in the promoter region of IFNB1. Moreover, we found that the expression of RNF215 negatively correlated with type I IFNs in patients with systemic lupus erythematosus, indicating that RNF215 plays an important role in the pathogenesis of autoimmune diseases. Collectively, our data identified RNF215 as a key negative regulator of type I IFNs and suggested RNF215 as a potential target for intervention in diseases with aberrant IFN production.

SHFL inhibits enterovirus A71 infection by triggering degradation of viral 3Dpol protein via the ubiquitin-proteasome pathway.

Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.

Neural progenitor cell pyroptosis contributes to Zika virus-induced brain atrophy and represents a therapeutic target.

Mounting evidence has associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly, which raises global alarm. Nonetheless, mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly are far from being understood. In this study, we discovered direct effects of ZIKV on neural progenitor cell development by inducing caspase-1- and gasdermin D (GSDMD)-mediated pyroptotic cell death, linking ZIKV infection with the development of microcephaly. Importantly, caspase-1 depletion or its inhibitor VX-765 treatment reduced ZIKV-induced inflammatory responses and pyroptosis, and substantially attenuated neuropathology and brain atrophy in vivo. Collectively, our data identify caspase-1- and GSDMD-mediated pyroptosis in neural progenitor cells as a previously unrecognized mechanism for ZIKV-related pathological effects during neural development, and also provide treatment options for ZIKV-associated diseases.

Tumour-associated macrophages as a novel target of VEGI-251 in cancer therapy.

Tumour-associated macrophages (TAMs), which possess M2-like characters and are derived from immature monocytes in the circulatory system, represent a predominant population of inflammatory cells in solid tumours. TAM infiltration in tumour microenvironment can be used as an important prognostic marker in many cancer types and is a potential target for cancer prevention or treatment. VEGI-251 not only is involved in the inhibition of tumour angiogenesis, but also participates in the regulation of host immunity. This work aimed to investigate the involvement of VEGI-251 in the regulation of specific antitumour immunity. We found that recombinant human VEGI-251(rhVEGI-251) efficiently mediated the elimination of TAMs in tumour tissue in mice, and induced apoptosis of purified TAMs in vitro. During this process, caspase-8 and caspase-3 were activated, leading to PARP cleavage and apoptosis. Most importantly, we further elucidated the mechanism underlying VEGI-251-triggered TAM apoptosis, which suggests that ASK1, an intermediate component of the VEGI-251, activates the JNK pathway via TRAF2 in a potentially DR3-dependent manner in the process of TAM apoptosis. Collectively, our findings provide new insights into the basic mechanisms underlying the actions of VEGI-251 that might lead to future development of antitumour therapeutic strategies using VEGI-251 to target TAMs.