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Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes severe and potentially fatal hemorrhagic fever in humans. Autophagy is a self-degradative process that can restrict viral replication at multiple infection steps. In this study, we evaluated the effects of RVFV-triggered autophagy on viral replication and immune responses. Our results showed that RVFV infection triggered autophagosome formation and induced complete autophagy. Impairing autophagy flux by depleting autophagy-related gene 5 ( ATG5 ), ATG7 , or sequestosome 1 ( SQSTM1 ) or treatment with autophagy inhibitors markedly reduced viral RNA synthesis and progeny virus production. Mechanistically, our findings demonstrated that the RVFV nucleoprotein (NP) C-terminal domain interacts with the autophagy receptor SQSTM1 and promotes the SQSTM1-microtubule-associated protein 1 light chain 3 B (LC3B) interaction and autophagy. Deletion of the NP C-terminal domain impaired the interaction between NP and SQSTM1 and its ability to trigger autophagy. Notably, RVFV-triggered autophagy promoted viral infection in macrophages but not in other tested cell types, including Huh7 hepatocytes and human umbilical vein endothelial cells, suggesting cell type specificity of this mechanism. It was further revealed that RVFV NP-triggered autophagy dampens antiviral innate immune responses in infected macrophages to promote viral replication. These results provide novel insights into the mechanisms of RVFV-triggered autophagy and indicate the potential of targeting the autophagy pathway to develop antivirals against RVFV. IMPORTANCE We showed that RVFV infection induced the complete autophagy process. Depletion of the core autophagy genes ATG5 , ATG7 , or SQSTM1 or pharmacologic inhibition of autophagy in macrophages strongly suppressed RVFV replication. We further revealed that the RVFV NP C-terminal domain interacted with SQSTM1 and enhanced the SQSTM1/LC3B interaction to promote autophagy. RVFV NP-triggered autophagy strongly inhibited virus-induced expression of interferon-stimulated genes in infected macrophages but not in other tested cell types. Our study provides novel insights into the mechanisms of RVFV-triggered autophagy and highlights the potential of targeting autophagy flux to develop antivirals against this virus.

To provides a reference basis for the apoptosis of breast cancer (BC) cells and the carcinogenesis of BC, the effects of 7, 12-dimethylbenz (a) anthracene (DMBA) on apoptosis regulators FasL and B-cell lymphoma-2 (Bcl-2) were investigated. In this study, 62 female C57BL/6 mice aged from 4 to 6 weeks were randomly divided into control group (CG) and test group (TG), with 31 mice in each group. The TG was given DMBA solution by gavage at a dose of 50 mg/kg, and the CG was given normal saline of equal volume. On the second day after the experiment, all the mice were killed by cervical dislocation. The morphology of the mammary gland was observed by hematoxylin-eosin (HE) staining, and the differences of FasL and Bcl-2 protein expression (PE) were detected by immunohistochemistry. The mRNA expression levels of FasL and Bcl-2 were detected by quantitative real-time PCR (qPCR). Breast cell apoptosis status of mice in the two groups was detected by the terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labelling (TUNEL) method. The results showed that after HE staining, the tumor cells in the TG were stacked up to form a substantial structure. The expression level of FasL protein in the CG was greatly lower than that in the TG, and the positive rate (PR) was 20.25%, which was greatly lower than that of 89.65% in the TG (P<0.01). The expression level of Bcl-2 protein in the mammary gland tissues (MGTs) of mice in the TG was greatly higher than that of the CG, and its PR was 87.96%, which was greatly higher than that of 31.48% in the CG (P<0.01). The expression levels of FasL mRNA in the MGTs of mice in the TG and CG were 5.82±4.37 and 1.27±0.12, respectively, and there was a statistically obvious difference (P<0.05). The mRNA expression levels of Bcl-2 in the TG and the CG were 18.97±2.65 and 2.02±0.54, respectively, and there was an extremely obvious difference (P<0.01). The apoptosis rate of mammary gland cells in the TG was (19.79±3.53) %, and that in the CG was (2.93±0.28) %, and there was an extremely obvious difference (P<0.01). It indicated that DMBA inhibited the apoptosis of BC cells by regulating the up-regulation of FasL and Bcl-2 expression.