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Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling.

Autophagy, mediated by a number of autophagy-related (ATG) proteins, plays an important role in the bulk degradation of cellular constituents. Beclin-1 (also known as Atg6 in yeast) is a core protein essential for autophagic initiation and other biological processes. The activity of Beclin-1 is tightly regulated by multiple post-translational modifications, including ubiquitination, yet the molecular mechanism underpinning its reversible deubiquitination remains poorly defined. Here, we identified ubiquitin-specific protease 19 (USP19) as a positive regulator of autophagy, but a negative regulator of type I interferon (IFN) signaling.USP19 stabilizes Beclin-1 by removing the K11-linked ubiquitin chains of Beclin-1 at lysine 437. Moreover, we foundthat USP19 negatively regulates type IIFNsignaling pathway, by blockingRIG-I-MAVSinteraction in a Beclin-1-dependent manner. Depletion of eitherUSP19 or Beclin-1 inhibits autophagic flux and promotes type IIFNsignaling as well as cellular antiviral immunity. Our findings reveal novel dual functions of theUSP19-Beclin-1 axis by balancing autophagy and the production of type IIFNs.

The novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency since patients were first detected in Wuhan, China. Thus far, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. The immune system and inflammation are proposed to play a central role in COVID-19 pathogenesis. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. Intravenous infusion of MSCs has shown promising results in COVID-19 treatment. Here, we report a case of a severe COVID-19 patient treated with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) from a healthy donor in Liaocheng People's Hospital, China, from February 24, 2020. The pulmonary function and symptoms of the patient with COVID-19 pneumonia was significantly improved in 2 days after hWJC transplantation, and recovered and discharged in 7 days after treatment. After treatment, the percentage and counts of lymphocyte subsets (CD3 + , CD4 + , and CD8 + T cell) were increased, and the level of IL-6, TNF-α, and C-reactive protein is significantly decreased after hWJC treatment. Thus, the intravenous transplantation of hWJCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially for the patients in a critically severe condition. This report highlights the potential of hWJC infusions as an effective treatment for COVID-19 pneumonia.

BackgroundIt is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism.MethodsMice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform.ResultsOur results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9.ConclusionsPinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.

Nuclear factor κB (NF-κB) is a key transcription factor in inflammatory immune responses and cell survival. Multiple types of ubiquitination play critical roles in the activation of NF-κB signaling, yet the molecular mechanisms responsible for their reversible deubiquitination are still poorly understood. In this study, we identified a member of the deubiquitinases family, ubiquitin-specific protease 18 (USP18), as a novel negative regulator in Toll-like receptor (TLR)-mediated NF-κB activation in human macrophages. USP18 is an interferon inducible gene, which is also upregulated by various TLR ligands in human monocytes and macrophages. Knockdown of USP18 enhanced the phosphorylation of IKK, the degradation of IκB, and augmented the expression of pro-inflammatory cytokines. Furthermore, USP18 interacted with TAK1-TAB1 complex and IKKα/β-NEMO complex, respectively. USP18 cleaved the K63-linked polyubiquitin chains attached to TAK1 in a protease-dependent manner. Moreover, USP18 targeted the IKK complex through the regulatory subunit NEMO of IKK, and specifically inhibited K63-linked ubiquitination of NEMO. Mutation analysis revealed direct binding of USP18 to the UBAN motif of NEMO. Our study has identified a previously unrecognized role for USP18 in the negative regulation of NF-κB activation by inhibiting K63-linked ubiquitination of TAK1 and NEMO through distinct mechanisms.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body’s immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.