Responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.

Viral infection triggers the formation of mitochondrial antiviral signaling protein ( MAVS ) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS ‐mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF 34 regulates immunity and mitophagy by targeting MAVS . RNF 34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG ‐I‐like receptor ( RLR )‐mediated antiviral immunity. Moreover, RNF 34 catalyzes the K27‐/K29‐linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP 52‐dependent autophagic degradation. Specifically, RNF 34 initiates the K63‐ to K27‐linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG ‐I stimulation. Notably, RNF 34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF 34‐mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.

The recently emerged pathogenic SARS-coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global pandemic. In this study, we show that SARS-CoV-2 infection was associated with clinically significant lower level of HDL cholesterol (HDL-C), which can be used as indicators of disease severity and poor prognosis. Importantly, we found the spike protein of SARS-CoV-2 (SARS-2-S) bound to HDL. Antagonists of HDL receptor-Scavenger receptor class B type I (SR-B1), strongly inhibited SARS-CoV-2 infection. Notably, the lipids transfer function of SR-B1 was indispensable for this inhibition, offering explanations for the reduced serum HDL level observed in COVID-19 patients. Basing on findings here, we speculate that SR-B1-mediated pulmonary HDL-vitamin E uptake could participate in mediating SARS-CoV-2 infection of lung cells, and the unique expression profile of SR-B1 may also affect SARS-CoV-2 cell and tissue tropism. These findings might help to provide further insights into viral transmission, pathological characteristics and reveal therapeutic targets.

The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor‐promoting inflammation by up‐regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi‐associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor‐associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose‐regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.

Highlights d MAVS promotes p53-dependent cell death in response to DNA damage d MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress d MAVS regulates p53 protein stability by blocking the formation of the p53-MDM2 complex d MAVS suppresses tumorigenesis in both p53-dependent and p53-independent manners

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.

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Nocardia is Gram-positive, weakly acid-fast, catalase-positive, nonmotile, branching rod-shaped aerobic bacteria, belonging to actinomycetales. 1,2 Nocardia widely exists in soil, water, air, and rotten plants. It is common in patients with T-cell deficiency (leukemia or AIDS), long-term usage of immunosuppressants (such as organ transplantation and malignant tumor), or patients with underlying diseases (such as diabetes and chronic kidney disease). [3][4][5][6] Pulmonary nocardiosis is a purulent and granulomatous disease caused by Nocardia invading the lung through respiratory tract inhalation or skin lesions. It can spread into the brain, kidney, and other organs by blood dissemination and even form life-threatening sepsis.The clinical manifestations of pulmonary nocardiosis are fever, cough, expectoration, dyspnea, chest pain, hemoptysis, weight loss, fatigue, and other symptoms. Pulmonary nocardiosis is commonly characterized by infiltrative lesions, cavities, nodules, or masses in lung segments or lobes in computed tomography. Because its clinical manifestations and imaging are not specific to common bacterial infection, pulmonary aspergillosis, lung cancer, pulmonary abscess,